Tetracyline Compounds

ABSTRACT

The present invention is directed to a compound represented by Structural Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (I) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (I), or a pharmaceutically acceptable salt thereof, and its therapeutic use.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/424,765, filed on Feb. 27, 2015, which is the U.S. National Stageof International Application No. PCT/US2013/057690, filed Aug. 30, 2013,which claims the benefit of U.S. Provisional Application No. 61/695,947,filed on Aug. 31, 2012. The entire teachings of the above applicationare incorporated herein by reference.

BACKGROUND OF THE INVENTION

The tetracyclines are broad spectrum anti-microbial agents that arewidely used in human and veterinary medicine. The total production oftetracyclines by fermentation or semi-synthesis is measured in thethousands of metric tons per year.

The widespread use of tetracyclines for therapeutic purposes has led tothe emergence of resistance to these antibiotics, even among highlysusceptible bacterial species. Therefore, there is need for newtetracycline analogs with improved antibacterial activities andefficacies against other tetracycline responsive diseases or disorders.

SUMMARY OF THE INVENTION

A first embodiment of the present invention is directed to a compoundrepresented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined and described herein.

Another embodiment of the present invention is directed to a compoundrepresented by Structural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined and described herein.

Another embodiment of the present invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent and a compound represented by Structural Formula (I)or (II), or a pharmaceutically acceptable salt thereof. Thepharmaceutical composition is used in therapy, such as treating aninfection (e.g., a bacterial infection) in a subject.

Another embodiment of the present invention is a method of treating aninfection (e.g., a bacterial infection) in a subject comprisingadministering to the subject an effective amount of a compoundrepresented by Structural Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the present invention is a method of preventing aninfection (e.g., a bacterial infection) in a subject comprisingadministering to the subject an effective amount of a compoundrepresented by Structural Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the present invention is the use of a compoundrepresented by Structural Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament fortreating an infection (e.g., a bacterial infection) in a subject.

Another embodiment of the present invention is the use of a compoundrepresented by Structural Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament forpreventing an infection (e.g., a bacterial infection) in a subject.

Another embodiment of the present invention is the use of a compoundrepresented by Structural Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof, in therapy, such as treating or preventing aninfection (e.g., a bacterial infection) in a subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound represented byStructural Formula (I), or a pharmaceutically acceptable salt thereof.The variables in Structural Formula (I) are described herein in thefollowing paragraphs. It is understood that the invention encompassesall combinations of the substituent variables (i.e., R¹, R², R³, etc.)defined herein.

A first embodiment of the invention is a compound having StructuralFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from N and C(R²);

-   -   each of R¹, R², R³, R⁵ and R⁶ is independently selected from        hydrogen, halo, —(C₁-C₆ alkyl), —OR^(A), —C(O)NR^(B)R^(B′),        NR^(B)R^(B′), S(O)₀₋₂R^(C), —(C₀-C₆ alkylene)-carbocyclyl, and        —(C₀-C₆ alkylene)-heterocyclyl; or    -   R¹ and R² are optionally taken together with atoms to which they        are bound to form a carbocyclyl or heterocyclyl ring; or    -   R² and R³ are optionally taken together with atoms to which they        are bound to form a carbocyclyl or heterocyclyl ring;    -   R⁴ is selected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-carbocyclyl, and —(C₀-C₆ alkylene)-heterocyclyl;    -   R^(4′) is selected from hydrogen, —(C₂-C₆ alkyl), S(O)₁₋₂R^(C),        —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl,        —C(O)—(C₁-C₆ alkyl), and —C(O)—(C₁-C₆ alkyl)-NR^(D)R^(E); or    -   R⁴ and R^(4′) are optionally taken together with the nitrogen        atom to which they are commonly bound to form a 4-8 membered        ring optionally comprising 1-2 additional heteroatoms        independently selected from N, O and S;    -   R^(6′) is selected from hydrogen, —(C₁-C₆ alkyl) and —(C₃-C₆        cycloalkyl);    -   each R^(A) is independently selected from hydrogen, —(C₁-C₆        alkyl), —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆        alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆        alkylene)-carbocyclyl, —C(O)—(C₀-C₆ alkylene)-heterocyclyl, and        —C(O)N(R^(D))(R^(E));    -   each R^(B) and each R^(B′) is independently selected from        hydrogen, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆        alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl,        —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆ alkylene)-carbocyclyl,        —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl),        —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H, —C(O)—(C₀-C₆        alkylene)-heterocyclyl, and —C(O)—(C₀-C₆        alkylene)-N(R^(D))(R^(E));    -   each R^(C) is independently selected from —(C₁-C₆ alkyl),        —(C₀-C₆ alkylene)-carbocyclyl and —(C₀-C₆        alkylene)-heterocyclyl; and    -   each R^(D) and each R^(E) is independently selected from        hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl, and        —(C₀-C₆ alkylene)-heterocyclyl,

wherein any alkyl, alkylene, carbocyclyl or heterocyclyl portion of R¹,R², R³, R⁴, R^(4′), R⁵, R⁶, R^(6′), R^(A), R^(B), R^(B′), R^(C), R^(D),or R^(E) or formed by taking R¹ and R², R² and R³, or R⁴ and R^(4′)together is optionally and independently substituted.

In a first aspect of the first embodiment:

-   -   any alkyl, or alkylene portion of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶        is optionally and independently substituted with one or more        substituents independently selected from halo, ═O, OR^(A),        NR^(B)R^(B′), and S(O)₀₋₂R^(C);    -   any alkyl or alkylene portion of R^(6′), R^(A), or R^(C), is        optionally and independently substituted with one or more        fluoro;    -   any carbocyclyl or heterocyclyl portion of any of R¹, R², R³,        R⁴, R^(4′), R⁵, R⁶, or any ring formed by taking together R¹ and        R², R² and R³ or R⁴ and R^(4′) is optionally and independently        substituted on a carbon atom with one or more substituents        independently selected from halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄        alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl), —(C₀-C₆        alkylene)-(4-13 membered heterocyclyl), OR^(A), —(C₀-C₆        alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);    -   any heterocyclyl portion of any of R¹, R², R³, R⁴, R^(4′), R⁵,        R⁶, or any ring formed by taking together R¹ and R², R² and R³        or R⁴ and R^(4′) is optionally and independently substituted on        a substitutable nitrogen atom with R^(F);    -   each R^(F) is independently selected from —(C₁-C₆ alkyl),        —(C₁-C₆ haloalkyl), —(C₁-C₆ hydroxyalkyl), —(C₀-C₆        alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl,        —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆ alkylene)-carbocyclyl,        —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl),        —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H, —C(O)—(C₀-C₆        alkylene)-heterocyclyl, —(C₀-C₆ alkylene)-C(O)₂—(C₁-C₆ alkyl),        —(C₁-C₆ alkylene)-NR^(B)R^(B′) and —C(O)N(R^(D))(R^(E));    -   any carbocyclyl or heterocyclyl portion of R^(A), R^(B), R^(B′),        R^(C), R^(D), R^(E), R^(F), any cycloalkyl portion of R^(6′), or        any substituent of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶ is optionally        and independently substituted on a carbon atom with a one or        more substituents independently selected from fluoro, chloro,        C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄        fluoroalkyl, ═O, —OH, —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄        alkyl)₂;    -   any heterocyclyl portion of R^(A), R^(B), R^(B′), R^(C), R^(D),        R^(E), R^(F), or any heterocyclyl substituent of R¹, R², R³, R⁴,        R^(4′), R⁵, or R⁶ is optionally substituted on a substitutable        nitrogen atom with —C₁-C₄ alkyl, or —S(O)₁₋₂—(C₁-C₄ alkyl). The        remaining variables are as described and defined in the first        embodiment.

In a second aspect of the first embodiment, the compound is other than:

or a salt of any of the foregoing. The remaining variables are asdescribed and defined in the first embodiment, or first aspect thereof.

In a third aspect of the first embodiment, each of R⁵, R⁶ and R^(6′) ishydrogen. The remaining variables are as described and defined in thefirst embodiment, or the first or second aspect thereof.

In a fourth aspect of the first embodiment, X is C(R²). The remainingvariables are as described and defined in the first embodiment, or thefirst, second or third aspect thereof.

In a fifth aspect of the first embodiment:

X is selected from N and C(R²);

each of R¹, R², R³, R⁵ and R⁶ is independently selected from hydrogen,halo, —(C₁-C₆ alkyl), —OR^(A), NR^(B)R^(B′), —C(O)NR^(B)R^(B′),S(O)₀₋₂R, —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl; or

R¹ and R² are optionally taken together with atoms to which they arebound to form a carbocyclyl or heterocyclyl ring; or

R² and R³ are optionally taken together with atoms to which they arebound to form a carbocyclyl or heterocyclyl ring;

R⁴ is selected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, and —(C₀-C₆ alkylene)-heterocyclyl;

R^(4′) is selected from hydrogen, —(C₂-C₆ alkyl), S(O)₁₋₂R^(C), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆alkyl), and —C(O)—(C₁-C₆ alkyl)-NR^(D)R^(E); or

R⁴ and R^(4′) are optionally taken together with the nitrogen atom towhich they are commonly bound to form a 4-8 membered ring optionallycomprising 1-2 additional heteroatoms independently selected from N, Oand S;

R^(6′) is selected from hydrogen, —(C₁-C₆ alkyl) and —(C₃-C₆cycloalkyl);

each R^(A) is independently selected from hydrogen, —(C₁-C₆ alkyl),—(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl,—C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)—(C₀-C₆alkylene)-heterocyclyl, and —C(O)N(R^(D))(R^(E));

each R^(B) and each R^(B′) is independently selected from hydrogen,—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl,—C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H,—C(O)—(C₀-C₆ alkylene)-heterocyclyl, and —C(O)N(R^(D))(R^(E));

each R^(C) is independently selected from —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl and —(C₀-C₆ alkylene)-heterocyclyl; and

each R^(D) and each R^(E) is independently selected from hydrogen,—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl;

wherein any alkyl, alkylene, carbocyclyl or heterocyclyl portion of R¹,R², R³, R⁴, R^(4′), R⁵, R⁶, R^(6′), R^(A), R^(B), R^(B′), R^(C), R^(D),or R^(E) or formed by taking R¹ and R², R² and R³, or R⁴ and R^(4′)together is optionally and independently substituted. The remainingvariables are as described and defined in the first embodiment, or thefirst, second, third or fourth aspect thereof.

In a sixth aspect of the first embodiment:

any alkyl or alkylene portion of R¹, R², R³, R⁴, R^(4′), R⁵, or R⁶ isoptionally and independently substituted with one or more substituentsindependently selected from halo, ═O, OR^(A), NR^(B)R^(B′), andS(O)₀₋₂R^(C);

any alkyl or alkylene portion of R^(6′), R^(A), or R^(C), is optionallyand independently substituted with one or more fluoro;

any carbocyclyl or heterocyclyl portion of any of R¹, R², R³, R⁴,R^(4′), R⁵, or R⁶, or any ring formed by taking together R¹ and R², R²and R³, or R⁴ and R^(4′) is optionally and independently substituted ona carbon atom with one or more substituents independently selected fromhalo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, C₃-C₁₀ carbocyclyl, a 4-13membered heterocyclyl, OR^(A), NR^(B)R^(B′), and S(O)₀₋₂R^(C);

any heterocyclyl portion of any of R¹, R², R³, R⁴, R^(4′), R⁵, or R⁶, orany ring formed by taking together R¹ and R², R² and R³, or R⁴ andR^(4′) is optionally and independently substituted on a substitutablenitrogen atom with R^(F);

each R^(F) is independently selected from —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆alkyl), —S(O)₁₋₂—(C₀-C₆ alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆alkylene)-carbocyclyl, —C(O)H, —C(O)—(C₀-C₆ alkylene)-heterocyclyl, and—C(O)N(R^(D))(R^(E));

any carbocyclyl or heterocyclyl portion of R^(A), R^(B), R^(B′), R^(C),R^(D), R^(E), R^(F), any cycloalkyl portion of R⁶, or any substituent ofR¹, R², R³, R⁴, R^(4′), R⁵, or R^(6′) is optionally and independentlysubstituted on a carbon atom with a one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl,—O—C₁-C₄ alkyl, —O—C₁-C₄ fluoroalkyl, ═O, —OH, —NH₂, —NH(C₁-C₄ alkyl),and —N(C₁-C₄ alkyl)₂; and

any heterocyclyl portion of R^(A), R^(B), R^(B′), R^(C), R^(D), R^(E),R^(F), or any heterocyclyl substituent of R¹, R², R³, R⁴, R^(4′), R⁵, orR⁶ is optionally substituted on a substitutable nitrogen atom with—C₁-C₄ alkyl, or —S(O)₁₋₂—(C₁-C₄ alkyl). The remaining variables are asdescribed and defined in the first embodiment, or the first, second,third, fourth or fifth aspect thereof.

In a seventh aspect of the first embodiment, X is N. The remainingvariables are as described and defined in the first embodiment, or thefirst, second, third, fourth, fifth or sixth aspect thereof.

In an eighth aspect of the first embodiment, R¹ is selected fromhydrogen, halo, —(C₁-C₆ alkyl) optionally substituted with one or moresubstituents independently selected from halo, —NR^(B)R^(B′),—C(O)NR^(B)R^(B′), —OR^(A), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl, wherein R^(A) is C₁-C₆ alkyl optionallysubstituted with one or more fluoro. The remaining variables are asdescribed and defined in the first embodiment, or the first, second,third, fourth, fifth, sixth or seventh aspect thereof.

In a ninth aspect of the first embodiment, R³ is selected from hydrogenand —N(R^(B))(R^(B′)), wherein R^(B) is hydrogen. The remainingvariables are as described and defined in the first embodiment, or thefirst, second, third, fourth, fifth, sixth, seventh or eighth aspectthereof.

A second embodiment of the invention is a compound of Structural Formula(I), wherein R⁴ is selected from hydrogen and —(C₁-C₆ alkyl); R^(4′) isselected from hydrogen, —(C₂-C₆ alkyl) optionally substituted with oneor more substituents independently selected from hydroxy and halo,—(C₃-C₆ cycloalkyl), —C(O)—(C₁-C₆ alkyl), —C(O)—(C₁-C₆alkylene)-N(R^(D))(R^(E)), and S(O)₁₋₂R^(C); or R⁴ and R^(4′) are takentogether with the nitrogen atom to which they are commonly bound to forma 4-6 membered ring optionally comprising 1-2 additional heteroatomsindependently selected from N, O and S; R^(C) is —(C₁-C₆ alkyl); andeach of R^(D) and R^(E) is independently selected from hydrogen and—(C₁-C₆ alkyl). The remaining variables are as described and defined inthe first embodiment, or any aspect thereof.

In a first aspect of the second embodiment, R⁴ is selected fromhydrogen, methyl, ethyl and propyl; and R^(4′) is selected fromhydrogen, ethyl, propyl, cyclopropyl, —C(O)CH₃, —C(O)CH₂N(CH₃)₂, and—S(O)₂CH₃. The remaining variables are as described and defined in thefirst embodiment, or any aspect thereof, or in the second embodiment.

In a second aspect of the second embodiment, R⁴ is selected fromhydrogen and —(C₁-C₆ alkyl); R^(4′) is selected from hydrogen, —(C₂-C₆alkyl), —(C₃-C₆ cycloalkyl), —C(O)—(C₁-C₆ alkyl), —C(O)—(C₁-C₆alkylene)-N(R^(D))(R^(E)), and S(O)₁₋₂R^(C); R^(C) is —(C₁-C₆ alkyl);and each of R^(D) and R^(E) is independently selected from hydrogen and—(C₁-C₆ alkyl). The remaining variables are as described and defined inthe first embodiment, or any aspect thereof, or the second embodiment,or first aspect thereof.

A third embodiment of the invention is a compound of Structural Formula(I), wherein R¹ is selected from hydrogen, halo, —(C₁-C₆ alkyl)optionally substituted with one or more substituents independentlyselected from halo, —NR^(B)R^(B′), —C(O)NR^(B)R^(B′), —OR^(A), —(C₀-C₆alkylene)-carbocyclyl, and —(C₀-C₆ alkylene)-heterocyclyl, wherein R^(A)is C₁-C₆ alkyl optionally substituted with one or more fluoro. Theremaining variables are as described and defined in the first or secondembodiment, or any aspect thereof.

In a first aspect of the third embodiment, X is C(R²). The remainingvariables are as described and defined in the first or secondembodiment, or any aspect thereof, or the third embodiment.

In a second aspect of the third embodiment, R¹ is selected fromhydrogen, fluoro, chloro, CF₃ and OCF₃. The remaining variables are asdescribed and defined in the first or second embodiment, or any aspectthereof, or the third embodiment, or first aspect thereof.

In a third aspect of the third embodiment, R¹ is selected from hydrogen,halo, —(C₁-C₆ alkyl) optionally substituted with one or moresubstituents independently selected from halo, and —OR^(A), whereinR^(A) is C₁-C₆ alkyl optionally substituted with one or more fluoro. Theremaining variables are as described and defined in the first or secondembodiment, or any aspect thereof, or the third embodiment, or first orsecond aspect thereof.

In a fourth aspect of the third embodiment, R¹ is selected fromhydrogen, fluoro, chloro, CF₃, OCH₃, OCF₃, N(CH₃)₂ and NHCH₃. Theremaining variables are as described and defined in the first or secondembodiment, or any aspect thereof, or the third embodiment, or first,second or third aspect thereof.

In a fifth aspect of the third embodiment, R¹ is selected from hydrogen,halo, —(C₁-C₆ alkyl) optionally substituted with halo, —NR^(B)R^(B′),—C(O)NR^(B)R^(B′), —OR^(A), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl, wherein R^(A) is C₁-C₆ alkyl optionallysubstituted with one or more fluoro. The remaining variables are asdescribed and defined in the first or second embodiment, or any aspectthereof, or the third embodiment, or first, second, third or fourthaspect thereof.

A fourth embodiment of the invention is a compound of Structural Formula(I), wherein R¹ and R² are taken together with the atoms to which theyare bound to form a nitrogen-containing heterocyclyl ring, wherein thering comprising R¹ and R² is optionally substituted on any substitutablenitrogen atom with C₁-C₄ alkyl; and optionally substituted on a carbonatom with NR^(B)R^(B′), wherein each of R^(B) and R^(B′) isindependently selected from hydrogen and C₁-C₆ alkyl. The remainingvariables are as described and defined in the first, second or thirdembodiment, or any aspect thereof.

In a first aspect of the fourth embodiment, R¹ and R² are taken togetherwith the carbon atoms to which they are bound to form:

wherein “

1” represents a point of attachment to the carbon atom bound to R¹ and “

2” represents a point of attachment to the carbon atom bound to R². Theremaining variables are as described and defined in the first, second orthird embodiment, or any aspect thereof, or the fourth embodiment.

In a second aspect of the fourth embodiment, X is C(R²). The remainingvariables are as described and defined in the first, second or thirdembodiment, or any aspect thereof, or the fourth embodiment, or thefirst aspect thereof.

In a third aspect of the fourth embodiment, X is C(R²); and R¹ and R²are taken together with the carbon atoms to which they are bound toform:

wherein “

1” represents a point of attachment to the carbon atom bound to R¹; “

2” represents a point of attachment to the carbon atom bound to R²; andf is 0 or 1. The remaining variables are as described and defined in thefirst, second or third embodiment, or any aspect thereof, or the fourthembodiment, or the first or second aspect thereof.

A fifth embodiment of the invention is a compound of Structural Formula(I), wherein R² is —(C₀-C₆ alkylene)-heterocyclyl optionally substitutedon a nitrogen atom with —(C₁-C₆ alkyl); —(C₀-C₆ alkylene)-carbocyclyl;or —(C₁-C₆)alkyl substituted with NR^(B)R^(B′). The remaining variablesare as described and defined in the first, second, third or fourthembodiment, or any aspect thereof.

In a first aspect of the fifth embodiment, R² is pyrrolidinyl optionallysubstituted on a nitrogen atom with C₁-C₄ alkyl or benzyl. The remainingvariables are as described and defined in the first, second, third orfourth embodiment, or any aspect thereof, or the fifth embodiment.

In a second aspect of the fifth embodiment, X is C(R²). The remainingvariables are as described and defined in the first, second, third orfourth embodiment, or any aspect thereof, or the fifth embodiment, orfirst aspect thereof.

In a third aspect of the fifth embodiment, R² is —(C₀-C₆alkylene)-heterocyclyl optionally substituted on a nitrogen atom with—(C₁-C₆ alkyl) or —(C₀-C₆ alkylene)-carbocyclyl. The remaining variablesare as described and defined in the first, second, third or fourthembodiment, or any aspect thereof, or the fifth embodiment, or first orsecond aspect thereof.

A sixth embodiment of the invention is a compound of Structural Formula(I), wherein R² and R³ are taken together with the atoms to which theyare bound to form a heterocyclyl, e.g., a nitrogen-containingheterocyclyl ring, wherein the ring comprising R² and R³ is optionallyand independently substituted on any substitutable nitrogen atom withC₁-C₄ alkyl. The remaining variables are as described and defined in thefirst, second, third, fourth or fifth embodiment, or any aspect thereof.

In a first aspect of the sixth embodiment, R² and R³ are taken togetherwith the atoms to which they are bound to form

wherein “

2” represents a point of attachment to the carbon atom bound to R², and“

3” represents a point of attachment to the carbon atom bound to R³. Theremaining variables are as described and defined in the first, second,third, fourth or fifth embodiment, or any aspect thereof, or the sixthembodiment.

In a second aspect of the sixth embodiment, R² and R³ are taken togetherwith the atoms to which they are bound to form

wherein “

2” represents a point of attachment to the carbon atom bound to R²; “

3” represents a point of attachment to the carbon atom bound to R³ and fis 0 or 1. The remaining variables are as described and defined in thefirst, second, third, fourth or fifth embodiment, or any aspect thereof,or the sixth embodiment, or first aspect thereof.

A seventh embodiment of the invention is a compound of StructuralFormula (I), wherein R³ is selected from hydrogen and —N(R^(B))(R^(B′)),wherein R^(B) is hydrogen and R^(B′) is —C(O)—(C₀-C₆alkylene)-heterocyclyl or —C(O)—(C₀-C₆ alkylene)-N(R^(D))(R^(E)). Theremaining variables are as described and defined in the first, second,third, fourth, fifth or sixth embodiment, or any aspect thereof.

In a first aspect of the seventh embodiment, R³ is selected fromhydrogen and

The remaining variables are as described and defined in the first,second, third, fourth, fifth or sixth embodiment, or any aspect thereof,or the seventh embodiment.

In a second aspect of the seventh embodiment, X is C(R²). The remainingvariables are as described and defined in the first, second, third,fourth, fifth or sixth embodiment, or any aspect thereof, or the seventhembodiment, or first aspect thereof.

In a third aspect of the seventh embodiment, R³ is selected fromhydrogen and —N(R^(B))(R^(B′)), wherein R^(B) is hydrogen and R^(B′) is—C(O)—(C₀-C₆ alkylene)-heterocyclyl. The remaining variables are asdescribed and defined in the first, second, third, fourth, fifth orsixth embodiment, or any aspect thereof, or the seventh embodiment, orfirst or second aspect thereof.

In one embodiment, the compound of the invention is one of the compoundsset forth in Table 1, or a pharmaceutically acceptable salt thereof. Thecompound designations used in Table 1 indicate the scheme used toprepare the compound. For example, Compound S8-4-3 was prepared inaccordance with Scheme 8 by selecting the appropriate pathway andreagents.

TABLE 1 Compound No. Compound Structure S3-7-1-A (diastereomer A)S3-7-1-B (diastereomer B)

S3-7-2

S3-7-3-A (diastereomer A) S3-7-3-B (diastereomer B)

S3-7-4-A (diastereomer A) S3-7-4-B (diastereomer B)

S3-7-5

S3-7-6-A (diastereomer A) S3-7-6-B (diastereomer B)

S3-7-7-A (diastereomer A) S3-7-7-B (diastereomer B)

S3-7-8-A (diastereomer A) S3-7-8-B (diastereomer B)

S3-7-9-A (diastereomer A) S3-7-9-B (diastereomer B)

S3-7-10-A (diastereomer A) S3-7-10-B (diastereomer B)

S3-7-11

S3-7-12

S3-7-13-A (diastereomer A) S3-7-13-B (diastereomer B)

S4-14-1 (diastereomer A)

S4-14-2 (diastereomer A)

S4-14-3 (diastereomer A)

S4-14-4 (diastereomer A)

S4-14-5-A (diastereomer A) S4-14-5-B (diastereomer B)

S4-14-7 (diastereomer A)

S4-14-8 (diastereomer A)

S4-14-9 (diastereomer A)

S4-14-10 (diastereomer A)

S4-14-11 (diastereomer A)

S4-14-12 (diastereomer A)

S4-14-13 (diastereomer A)

S4-14-14-A (diastereomer A) S4-14-14-B (diastereomer B)

S4-14-16 (diastereomer A)

S4-14-17 (diastereomer A)

S4-14-18 (diastereomer A)

S5-10-1-A (diastereomer A) S5-10-1-B (diastereomer B)

S5-10-1-2-A (diastereomer A) S5-10-1-2-B (diastereomer B)

S5-10-3-A (diastereomer A) S5-10-3-B (diastereomer B)

S5-10-4-A (diastereomer A) S5-10-4-B (diastereomer B)

S6-6-1 (single diastereomer)

S6-6-2 (single diastereomer)

S6-6-3 (single diastereomer)

S7-14-1-A (diastereomer A) S7-14-1-8 (diastereomer B)

S7-14-2-A (diastereomer A)

S7-14-3-A (diastereomer A)

S8-4-1

S8-4-2

S8-4-3

S9-4-1

S9-5-1

S9-5-2

S9-5-3

S9-5-4

S9-5-5

S9-5-6

S10-4-1 (single diastereomer)

S10-4-2 (single diastereomer)

S10-4-3 (single diastereomer)

S11-3-1

S11-3-2

S11-3-3

S12-8-1-A (diastereomer A) S12-8-1-B (diastereomer B)

S12-8-2-A (diastereomer A)

S12-8-3-A (diastereomer A) S12-8-3-B) (diastereomer B)

S12-8-4-A (diastereomer A)

S12-8-5-A (diastereomer A)

S12-8-6-A (diastereomer A) S12-8-6-B (diastereomer B)

S12-8-7-A (diastereomer A)

S12-8-8-A (diastereomer A)

S13-5-1

S13-5-2

S14-8-1

S14-8-2

S14-8-3A (diastereomer A) S14-8-3-B (diastereomer B)

S15-10-1

S15-10-2

S15-10-3-A (diastereomer A) S15-10-3-B (diastereomer B)

S16-7-1 (single diastereomer)

S16-7-2 (single diastereomer)

S16-7-3 (single diastereomer)

S16-7-4 (single diastereomer)

S16-7-5 (single diastereomer)

S16-7-6 (single diastereomer)

S17-3-1

S17-3-2

S17-3-3

S17-3-4

S17-3-5

S17-3-6

S17-3-7

S17-3-8

S17-3-9

S17-3-10

S17-3-11

S18-5-1-1

S18-5-1-2

S18-5-2-1

S18-5-2-2

S19--7-1-B (diastereomer B)

S19-7-2

S19-7-3-A (diastereomer A) S19-7-3-B (diastereomer B)

S19-7-4-A (diastereomer A) S19-7-4-B (diastereomer B)

S19-7-5-A (diastereomer A) S19-7-5-B (diastereomer B)

S19-7-6

S19-7-7-A (diastereomer A) S19-7-7-B (diastereomer B)

S20-4-1 (single diastereomer)

S20-4-2 (single diastereomer)

S20-4-3 (single diastereomer)

S20-4-4 (single diastereomer)

S21-5-1

S21-5-2

S21-5-3

S21-5-4

An eighth embodiment of the invention is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are taken together with atoms to which they are bound to forma carbocyclyl or heterocyclyl ring and R³ is selected from hydrogen,halo, —(C₁-C₆ alkyl), —OR^(A), —C(O)NR^(B)R^(B′), NR^(B)R^(B′),S(O)₀₋₂R^(C), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl; or

R² and R³ are taken together with atoms to which they are bound to forma carbocyclyl or heterocyclyl ring and R¹ is selected from hydrogen,halo, —(C₁-C₆ alkyl), —OR^(A), —C(O)NR^(B)R^(B′), NR^(B)R^(B′),S(O)₀₋₂R^(C), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl;

each of R⁵ and R⁶ is independently selected from hydrogen, halo, —(C₁-C₆alkyl), —OR^(A), —C(O)NR^(B)R^(B′), NR^(B)R^(B′), S(O)₀₋₂R^(C), —(C₀-C₆alkylene)-carbocyclyl, and —(C₀-C₆ alkylene)-heterocyclyl;

R^(6′) is selected from hydrogen, —(C₁-C₆ alkyl) and —(C₃-C₆cycloalkyl);

each R^(A) is independently selected from hydrogen, —(C₁-C₆ alkyl),—(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl,—C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)—(C₀-C₆alkylene)-heterocyclyl, and —C(O)N(R^(D))(R^(E));

each R^(B) and each R^(B′) is independently selected from hydrogen,—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl,—C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H,—C(O)—(C₀-C₆ alkylene)-heterocyclyl, and —C(O)—(C₀-C₆alkylene)-N(R^(D))(R^(E));

each R^(C) is independently selected from —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl and —(C₀-C₆ alkylene)-heterocyclyl; and

each R^(D) and each R^(E) is independently selected from hydrogen,—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl, wherein any alkyl, alkylene, carbocyclyl orheterocyclyl portion of R¹, R², R³, R⁵, R⁶, R^(6′), R^(A), R^(B),R^(B′), R^(C), R^(D), or R^(E) Or formed by taking R¹ and R² or R² andR³ together is optionally and independently substituted. Alternativevalues for the variables in Formula II are as described and defined inthe first through seventh embodiments, or any aspect thereof.

In a first aspect of the eighth embodiment, the compound is representedby Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

each R⁷, if present, is independently selected from halo, ═O, C₁-C₄fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl),—(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A), —(C₀-C₆alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);

p is 0, 1, 2, 3 or 4;

Y is C(O) or C(R⁸)₂ wherein each R⁸ is independently selected fromhydrogen, —(C₁-C₆)alkyl and —(C₃-C₆ cycloalkyl); and

f is 0 or 1. The remaining variables are as described and defined in thefirst through seventh embodiments, or any aspect thereof, or the eighthembodiment.

In a further aspect of the first aspect of the eighth embodiment, p is0. The remaining variables are as described and defined in the firstthrough seventh embodiments, or any aspect thereof, or the eighthembodiment, or first aspect thereof.

In a second aspect of the eighth embodiment, the compound is representedby Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀carbocyclyl), —(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A),—(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C); and Y is C(O) orC(R⁸)₂ wherein each R⁸ is independently selected from hydrogen,—(C₁-C₆)alkyl and —(C₃-C₆ cycloalkyl). The remaining variables are asdescribed and defined in the first through seventh embodiments, or anyaspect thereof, or the eighth embodiment, or first aspect thereof.

In a third aspect of the eighth embodiment, the compound is representedby Formula IIb-1:

or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀carbocyclyl), —(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A),—(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C). The remainingvariables are as described and defined in the first through seventhembodiments, or any aspect thereof, or the eighth embodiment, or firstor second aspect thereof.

In a fourth aspect of the eighth embodiment, the compound is representedby Formula IId:

or a pharmaceutically acceptable salt thereof, wherein:

each R⁷ and R⁸, if present, is independently selected from halo, ═O,C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, C₃-C₁₀ carbocyclyl, a 4-13 memberedheterocyclyl, OR^(A), —(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2; and

each f is independently 0 or 1. The remaining variables are as describedand defined in the first through seventh embodiments, or any aspectthereof, or the eighth embodiment, or first through third aspectsthereof.

In a further aspect of the fourth aspect of the eighth embodiment, p andq are each 0. The remaining variables are as described and defined inthe first through seventh embodiments, or any aspect thereof, or theeighth embodiment, or first through fourth aspects thereof.

In a fifth aspect of the eighth embodiment, each R^(F) is independentlyselected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₁-C₆ hydroxyalkyl),—(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —(C₀-C₆alkylene)-C(O)₂—(C₁-C₆ alkyl) and —(C₁-C₆ alkylene)-NR^(B)R^(B′). Theremaining variables are as described and defined in the first throughseventh embodiments, or any aspect thereof, or the eighth embodiment, orfirst through fourth aspects thereof.

In a sixth aspect of the eighth embodiment, each f is 0. The remainingvariables are as described and defined in the first through seventhembodiments, or any aspect thereof, or the eighth embodiment, or firstthrough fifth aspects thereof.

In a seventh aspect of the eighth embodiment, each f is 1. The remainingvariables are as described and defined in the first through seventhembodiments, or any aspect thereof, or the eighth embodiment, or firstthrough sixth aspects thereof.

In an eighth aspect of the eighth embodiment, the ring formed by R¹ andR² or R² and R³ together with atoms to which they are bound is a 4-7membered non-aromatic heterocyclic ring optionally containing 1-2heteroatoms independently selected from N, S and O. The remainingvariables are as described and defined in the first through seventhembodiments, or any aspect thereof, or the eighth embodiment, or firstthrough seventh aspects thereof.

In a ninth aspect of the eighth embodiment:

-   -   any alkyl, or alkylene portion of R¹, R², R³, R⁵, R⁶ is        optionally and independently substituted with one or more        substituents independently selected from halo, ═O, OR^(A),        NR^(B)R^(B′), and S(O)₀₋₂R^(C);    -   any alkyl or alkylene portion of R^(6′), R^(A), or R^(C), is        optionally and independently substituted with one or more        fluoro;    -   any carbocyclyl or heterocyclyl portion of any of R¹, R², R³,        R⁵, R⁶, or any ring formed by taking together R¹ and R² or R²        and R³ is optionally and independently substituted on a carbon        atom with one or more substituents independently selected from        halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆        alkylene)-(C₃-C₁₀ carbocyclyl), —(C₀-C₆ alkylene)-(4-13 membered        heterocyclyl), OR^(A), —(C₀-C₆ alkylene)-NR^(B)R^(B′), and        S(O)₀₋₂R^(C);    -   any heterocyclyl portion of any of R¹, R², R³, R⁵, R⁶, or any        ring formed by taking together R¹ and R² or R² and R³ is        optionally and independently substituted on a substitutable        nitrogen atom with R^(F);    -   each R^(F) is independently selected from —(C₁-C₆ alkyl),        —(C₁-C₆ haloalkyl), —(C₁-C₆ hydroxyalkyl), —(C₀-C₆        alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl,        —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆ alkylene)-carbocyclyl,        —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl),        —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H, —C(O)—(C₀-C₆        alkylene)-heterocyclyl, —(C₀-C₆ alkylene)-C(O)₂—(C₁-C₆ alkyl),        —(C₁-C₆ alkylene)-NR^(B)R^(B′) and —C(O)N(R^(D))(R^(E));    -   any carbocyclyl or heterocyclyl portion of R^(A), R^(B), R^(B′),        R^(C), R^(D), R^(E), R^(F), any cycloalkyl portion of R^(6′), or        any substituent of R¹, R², R³, R⁵, R⁶ is optionally and        independently substituted on a carbon atom with a one or more        substituents independently selected from fluoro, chloro, C₁-C₄        alkyl, C₁-C₄ fluoroalkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄ fluoroalkyl,        ═O, —OH, —NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂;

any heterocyclyl portion of R^(A), R^(B), R^(B′), R^(C), R^(D), R^(E),R^(F), or any heterocyclyl substituent of R¹, R², R³, R⁵, or R⁶ isoptionally substituted on a substitutable nitrogen atom with —C₁-C₄alkyl, or —S(O)₁₋₂—(C₁-C₄ alkyl). The remaining variables are asdescribed and defined in the first through seventh embodiments, or anyaspect thereof, or the eighth embodiment, or first through eighthaspects thereof.

In a tenth aspect of the eighth embodiment, the compound is representedby Formula IIa-1:

or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1 andR⁷, if present, is —C₁-C₆ alkyl. The remaining variables are asdescribed and defined in the first through seventh embodiments, or anyaspect thereof, or the eighth embodiment, or first through ninth aspectsthereof.

In an eleventh aspect of the eighth embodiment, the compound isrepresented by Formula IIb-2:

or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀carbocyclyl), —(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A),—(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C). The remainingvariables are as described and defined in the first through seventhembodiments, or any aspect thereof, or the eighth embodiment, or firstthrough tenth aspects thereof.

In a twelfth aspect of the eighth embodiment, any carbocyclyl orheterocyclyl portion of any ring formed by taking together R¹ and R² orR² and R³ is optionally and independently substituted on a carbon atomwith one or more substituents independently selected from halo, ═O,C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl),—(C₀-C₆ alkylene)-(4-13 membered heterocyclyl) and —(C₀-C₆alkylene)-NR^(B)R^(B′). The remaining variables are as described anddefined in the first through seventh embodiments, or any aspect thereof,or the eighth embodiment, or first through eleventh aspects thereof.

A ninth embodiment of the invention is a compound represented by FormulaIIc:

or a pharmaceutically acceptable salt thereof, wherein R⁷, if present,is selected from halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆alkylene)-(C₃-C₁₀ carbocyclyl), —(C₀-C₆ alkylene)-(4-13 memberedheterocyclyl), OR^(A), —(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);p is 0 or 1; and f is 0 or 1. Values and alternative values for theremaining variables are as described and defined in the first througheighth embodiments, or any aspect thereof.

In a first aspect of the ninth embodiment, p is 1. The remainingvariables are as described and defined in the first through eighthembodiments, or any aspect thereof, or the ninth embodiment.

In a second aspect of the ninth embodiment, the compound is representedby Formula IIc-1:

or a pharmaceutically acceptable salt thereof. The variables are asdescribed and defined in the first through eighth embodiments, or anyaspect thereof, or the ninth embodiment, or first aspect thereof.

In a third aspect of the ninth embodiment, R⁷, if present, is selectedfrom —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl), —(C₀-C₆ alkylene)-(4-13membered heterocyclyl) and —(C₀-C₆ alkylene)-NR^(B)R^(B′). The remainingvariables are as described and defined in the first through eighthembodiments, or any aspect thereof, or the ninth embodiment, or first orsecond aspect thereof.

In a fourth aspect of the ninth embodiment, R⁷, if present, is—NR^(B)R^(B′). The remaining variables are as described and defined inthe first through eighth embodiments, or any aspect thereof, or theninth embodiment, or first through third aspects thereof.

In one embodiment, the compound of the invention is one of the compoundsset forth in Tables 2A-2F hereinbelow, or a pharmaceutically acceptablesalt thereof.

A tenth embodiment of the invention is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

each R⁷, if present, is independently selected from halo, ═O, C₁-C₄fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl),—(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A), —(C₀-C₆alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);

p is 0, 1, 2, 3 or 4;

Y is C(O) or C(R⁸)₂ wherein each R⁸ is independently selected fromhydrogen, —(C₁-C₆)alkyl and —(C₃-C₆ cycloalkyl); and

f is 0 or 1. Values and alternative values for the variables are asdescribed and defined in the first through ninth embodiments, or anyaspect thereof.

In a first aspect of the tenth embodiment, p is 0. The remainingvariables are as described and defined in the first through ninthembodiments, or any aspect thereof, or the tenth embodiment.

In a second aspect of the tenth embodiment, each R⁸ is hydrogen. Theremaining variables are as described and defined in the first throughninth embodiments, or any aspect thereof, or the tenth embodiment, orfirst aspect thereof.

An eleventh embodiment of the invention is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X is C(R²); R² isoptionally substituted —(C₀-C₁ alkylene)-(4-6-membered heterocyclyl).Values and alternative values for the variables are as described anddefined in the first through tenth embodiments, or any aspect thereof.

In a first aspect of the eleventh embodiment, R³ is hydrogen. Theremaining variables are as described and defined in the first throughtenth embodiments, or any aspect thereof, or the eleventh embodiment.

In a second aspect of the eleventh embodiment, R² is optionallysubstituted —(C₀-C₁ alkylene)-pyrrolidinyl. The remaining variables areas described and defined in the first through tenth embodiments, or anyaspect thereof, or the eleventh embodiment, or first aspect thereof.

In a third aspect of the eleventh embodiment, R² is optionallysubstituted pyrrolidin-2-yl. The remaining variables are as describedand defined in the first through tenth embodiments, or any aspectthereof, or the eleventh embodiment, or first or second aspect thereof.

In a fourth aspect of the eleventh embodiment, R² is optionallysubstituted —(C₁ alkylene)-(pyrrolidin-1-yl). The remaining variablesare as described and defined in the first through tenth embodiments, orany aspect thereof, or the eleventh embodiment, or first through thirdaspects thereof.

A twelfth embodiment of the invention is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

each R⁷ and R⁸, if present, is independently selected from halo, ═O,C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, C₃-C₁₀ carbocyclyl, a 4-13 memberedheterocyclyl, OR^(A), —(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2; and

each f is independently 0 or 1. Values and alternative values for thevariables are as described and defined in the first through eleventhembodiments, or any aspect thereof.

In a first aspect of the twelfth embodiment, p and q are each 0. Theremaining variables are as described and defined in the first througheleventh embodiments, or any aspect thereof, or the twelfth embodiment.

In a second aspect of the twelfth embodiment, R³ is hydrogen. Theremaining variables are as described and defined in the first througheleventh embodiments, or any aspect thereof, or the twelfth embodiment,or first aspect thereof.

A thirteenth embodiment of the invention is a compound represented byFormula Ic:

or a pharmaceutically acceptable salt thereof, wherein R⁷, if present,is selected from halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆alkylene)-(C₃-C₁₀ carbocyclyl), —(C₀-C₆ alkylene)-(4-13 memberedheterocyclyl), OR^(A), —(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C);p is 0 or 1; and f is 0 or 1. Values and alternative values for theremaining variables are as described and defined in the first throughtwelfth embodiments, or any aspect thereof.

In a first aspect of the thirteenth embodiment, p is 1. The remainingvariables are as described and defined in the first through twelfthembodiments, or any aspect thereof, or the thirteenth embodiment.

In a second aspect of the thirteenth embodiment, the compound isrepresented by Formula Ic-1:

or a pharmaceutically acceptable salt thereof. The variables are asdescribed and defined in the first through twelfth embodiments, or anyaspect thereof, or the thirteenth embodiment, or first aspect thereof.

In a third aspect of the thirteenth embodiment, R⁷, if present, isselected from —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl), —(C₀-C₆alkylene)-(4-13 membered heterocyclyl) and —(C₀-C₆alkylene)-NR^(B)R^(B′). The remaining variables are as described anddefined in the first through twelfth embodiments, or any aspect thereof,or the thirteenth embodiment, or first or second aspect thereof.

In a fourth aspect of the thirteenth embodiment, R⁷, if present, is—NR^(B)R^(B′). The remaining variables are as described and defined inthe first through twelfth embodiments, or any aspect thereof, or thethirteenth embodiment, or first through third aspects thereof.

In a fourteenth embodiment of the invention, the compound is a compoundrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X is N and R³ is hydrogen. Values and alternative values for theremaining variables are as described and defined in the first throughthirteenth embodiments, or any aspect thereof.

In a first aspect of the fourteenth embodiment, R¹ is selected fromhydrogen and NR^(B)R^(B′). The remaining variables are as described anddefined in the first through thirteenth embodiments, or any aspectthereof, or the fourteenth embodiment.

A fifteenth embodiment of the invention is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X is C(R²) and R² is(C₁ alkylene)-NR^(B)R^(B′). Values and alternative values for theremaining variables are as described and defined in the first throughfourteenth embodiments, or any aspect thereof.

In a first aspect of the fifteenth embodiment, R^(B) and R^(B′) are eachindependently selected from hydrogen and —(C₁-C₆ alkyl). The remainingvariables are as described and defined in the first through fourteenthembodiments, or any aspect thereof, or the fifteenth embodiment.

A sixteenth embodiment of the invention is a compound represented byFormula Id:

or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀carbocyclyl), —(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A),—(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C). Values and alternativevalues for the variables are as defined in the first through fifteenthembodiments, or any aspect thereof.

In a first aspect of the sixteenth embodiment, R⁷ is 4-6 memberedheterocyclyl or —NR^(B)R^(B′). The remaining variables are as describedand defined in the first through fifteenth embodiments, or any aspectthereof, or the sixteenth embodiment.

A seventeenth embodiment of the invention is a compound represented byFormula Ie:

or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom halo, ═O, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀carbocyclyl), —(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A),—(C₀-C₆ alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C). Values and alternativevalues for the variables are as defined in the first through sixteenthembodiments, or any aspect thereof.

In a first aspect of the seventeenth embodiment, R⁷ is 4-6 memberedheterocyclyl or —NR^(B)R^(B′). The remaining variables are as describedand defined in the first through sixteenth embodiments, or any aspectthereof, or the seventeenth embodiment.

In an additional aspect of any of the preceding embodiments, or anyaspect thereof, each R^(A) is independently selected from hydrogen,—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆alkylene)-heterocyclyl, —S—(C₁-C₆ alkyl), —S—(C₀-C₆alkylene)-carbocyclyl, —S—(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)—(C₀-C₆alkylene)-heterocyclyl, and —C(O)N(R^(D))(R^(E)).

The compounds in Tables 1 and 2A-2F contain stereocenters for which thestereochemistry is not indicated. The compounds of the inventionencompass all possible diastereomers resulting from all possibleconfigurations at these stereocenters.

The chemical moiety indicated when f in —N(R^(F))_(f)— is 0 in thestructural formulae described herein is —N(H)—. Similarly, when q in—(R⁸)_(q) is 0, it means that the carbon atom attached to —(R⁸)_(q) isattached to two hydrogen atoms.

“Alkyl” means an optionally substituted saturated aliphatic branched orstraight-chain monovalent hydrocarbon radical having the specifiednumber of carbon atoms. Thus, “(C₁-C₆) alkyl” means a radical havingfrom 1-6 carbon atoms in a linear or branched arrangement.“(C₁-C₆)alkyl” includes methyl, ethyl, propyl, butyl, pentyl and hexyl.

“Alkylene” means an optionally substituted saturated aliphatic branchedor straight-chain divalent hydrocarbon radical having the specifiednumber of carbon atoms. Thus, “(C₁-C₆)alkylene” means a divalentsaturated aliphatic radical having from 1-6 carbon atoms in a lineararrangement, e.g., —[(CH₂)_(n)]—, where n is an integer from 1 to 6,“(C₁-C₆)alkylene” includes methylene, ethylene, propylene, butylene,pentylene and hexylene. Alternatively, “(C₁-C₆)alkylene” means adivalent saturated radical having from 1-6 carbon atoms in a branchedarrangement, for example: —[(CH₂CH₂CH₂CH₂CH(CH₃)]—,—[(CH₂CH₂CH₂CH₂C(CH₃)₂]—, —[(CH₂C(C H₃)₂CH(CH₃))]—, and the like. Aspecific branched C₃-alkylene is

and a specific C₄-alkylene is

“Aryl” or “aromatic” means an aromatic monocyclic or polycyclic (e.g.bicyclic or tricyclic) carbocyclic ring system. In one embodiment,“aryl” is a 6-12 membered monocylic or bicyclic system. Aryl systemsinclude, but not limited to, phenyl, naphthalenyl, fluorenyl, indenyl,azulenyl, and anthracenyl.

“Carbocyclyl” means a cyclic group, wherein all ring atoms in the ringbound to the rest of the compound (also known as the “first ring”) arecarbon atoms. “Carbocyclyl” includes 3-12 membered saturated orunsaturated aliphatic cyclic hydrocarbon rings or 6-12 membered arylrings. A carbocyclyl moiety can be monocyclic, fused bicyclic, bridgedbicyclic, spiro bicyclic, or polycyclic.

Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclichydrocarbon rings or aromatic hydrocarbon rings having the specifiednumber of carbon atoms. Monocyclic carbocyclyls include cycloalkyl,cycloalkenyl, cycloalkynyl and phenyl.

A fused bicyclic carbocyclyl has two rings which have two adjacent ringatoms in common. The first ring is a monocyclic carbocyclyl and the ringfused to the first ring (also known as the “second ring”) is amonocyclic carbocyclyl or a monocyclic heterocyclyl.

A bridged bicyclic carbocyclyl has two rings which have three or moreadjacent ring atoms in common. The first ring is a monocycliccarbocyclyl and the second ring is a monocyclic carbocyclyl or amonocyclic heterocyclyl.

A spiro bicyclic carbocyclyl has two rings which have only one ring atomin common. The first ring is a monocyclic carbocyclyl and the secondring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.

Polycyclic carbocyclyls have more than two rings (e.g., three ringsresulting in a tricyclic ring system) and adjacent rings have at leastone ring atom in common. The first ring is a monocyclic carbocyclyl andthe remainder of the ring structures are monocyclic carbocyclyls ormonocyclic heterocyclyls. Polycyclic ring systems include fused, bridgedand spiro ring systems. A fused polycyclic ring system has at least tworings that have two adjacent ring atoms in common. A spiro polycyclicring system has at least two rings that have only one ring atom incommon. A bridged polycyclic ring system has at least two rings thathave three or more adjacent ring atoms in common.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ring. Thus,“C₃-C₇ cycloalkyl” means a hydrocarbon radical of a (3-7 membered)saturated aliphatic cyclic hydrocarbon ring. A C₃-C₇ cycloalkylincludes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

“Cycloalkene” means an aliphatic cyclic hydrocarbon ring having one ormore double bonds in the ring.

“Cycloalkyne” means an aliphatic cyclic hydrocarbon ring having one ormore triple bonds in the ring.

“Hetero” refers to the replacement of at least one carbon atom member ina ring system with at least one heteroatom selected from N, S, and O.“Hetero” also refers to the replacement of at least one carbon atommember in a acyclic system. When one heteroatom is S, it can beoptionally mono- or di-oxygenated (i.e. —S(O)— or —S(O)₂—). A heteroring system or a hetero acyclic system may have 1, 2, 3 or 4 carbon atommembers replaced by a heteroatom.

“Heterocyclyl” means a cyclic 4-12 membered saturated or unsaturatedaliphatic or aromatic ring system containing 1, 2, 3, 4 or 5 heteroatomsindependently selected from N, O and S, wherein the first ring comprisesa ring heteroatom. When one heteroatom is S, it can be optionally mono-or di-oxygenated (i.e. —S(O)— or —S(O)₂—). The heterocyclyl can bemonocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic orpolycyclic.

“Saturated heterocyclyl” means an aliphatic heterocyclyl group withoutany degree of unsaturation (i.e., no double bond or triple bond). It canbe monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic orpolycyclic.

Examples of monocyclic saturated heterocyclyls include, but are notlimited to, azetidine, pyrrolidine, piperidine, piperazine, azepane,hexahydropyrimidine, tetrahydrofuran, tetrahydropyran, morpholine,thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-thiazine,tetrahydro-2H-1,2-thiazine 1,1-dioxide, isothiazolidine, isothiazolidine1,1-dioxide.

A fused bicyclic heterocyclyl has two rings which have two adjacent ringatoms in common. The first ring is a monocyclic heterocyclyl and thesecond ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl)or a monocyclic heterocyclyl. For example, the second ring is a(C₃-C₆)cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. Alternatively, the second ring is phenyl. Examples of fusedbicyclic heterocyclyls include, but are not limited to,octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline,2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole,2,3-dihydrobenzo[d]thiazole, octahydrobenzo[d]oxazole,octahydro-1H-benzo[d]imidazole, octahydrobenzo[d]thiazole,octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3.1.0]hexane, and3-azabicyclo[3.2.0]heptane.

A spiro bicyclic heterocyclyl has two rings which have only one ringatom in common. The first ring is a monocyclic heterocyclyl and thesecond ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl)or a monocyclic heterocyclyl. For example, the second ring is a(C₃-C₆)cycloalkyl. Alternatively, the second ring is phenyl. Example ofspiro bicyclic heterocyclyl includes, but are not limited to,azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azasprio[4.5]decane,8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecaneand 3,9-diazaspiro[5.5]undecane.

A bridged bicyclic heterocyclyl has two rings which have three or moreadjacent ring atoms in common. The first ring is a monocyclicheterocyclyl and the other ring is a monocyclic carbocycle (such as acycloalkyl or phenyl) or a monocyclic heterocyclyl. Examples of bridgedbicyclic heterocyclyls include, but are not limited to,azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane,azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane,6-azabicyclo[3.2.1]octane and azabicyclo[2.2.2]octane,2-azabicyclo[2.2.2]octane.

Polycyclic heterocyclyls have more than two rings, wherein the firstring is a heterocyclyl (e.g., three rings resulting in a tricyclic ringsystem) and adjacent rings having at least one ring atom in common andare heterocyclyl or carbocyclyl. Polycyclic ring systems include fused,bridged and spiro ring systems. A fused polycyclic ring system has atleast two rings that have two adjacent ring atoms in common. A spiropolycyclic ring system has at least two rings that have only one ringatom in common. A bridged polycyclic ring system has at least two ringsthat have three or more adjacent ring atoms in common. Examples ofpolycyclic heterocyclyls include

“Heteroaryl” or “heteroaromatic ring” means a 5-12 membered monovalentheteroaromatic monocyclic or bicylic ring radical. A heteroaryl contains1, 2, 3 or 4 heteroatoms independently selected from N, O, and S.Heteroaryls include, but are not limited to furan, oxazole, thiophene,1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2,5-thiadiazole1,1-dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,5-triazine, imidazole,isothiazole, isoxazole, pyrazole, pyridazine, pyridine,pyridine-N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, andthiazole. Bicyclic heteroaryl rings include, but are not limited to,bicyclo[4.4.0] and bicyclo[4.3.0] fused ring systems such as indolizine,indole, isoindole, indazole, benzimidazole, benzthiazole, purine,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,quinoxaline, 1,8-naphthyridine, and pteridine.

“Halogen” used herein refers to fluorine, chlorine, bromine, or iodine.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom.“(C₁-C₆)-alkoxy” includes methoxy, ethoxy, propoxy, butoxy, pentoxy andhexoxy.

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groupswhere each halogen is independently selected from fluorine, chlorine,and bromine.

“Halogen” and “halo” are interchangeably used herein and each refers tofluorine, chlorine, bromine, or iodine.

“Fluoro” means —F.

“Chloro” means —Cl.

As used herein, “fluoro-substituted-(C₁-C₄)alkyl” or “C₁-C₄ fluoroalkyl”means a (C₁-C₄)alkyl substituted with one or more —F groups. Examples offluoro-substituted-(C₁-C₄)alkyl include, but are not limited to, —CF₃,—CH₂CF₃, —CH₂CF₂H, —CH₂CH₂F and —CH₂CH₂CF₃.

“Hydroxyalkyl,” as used herein, refers to an alkyl group substitutedwith one or more hydroxyls. Hydroxyalkyl includes mono, poly, andperhydroxyalkyl groups. Examples of hydroxyalkyls include —CH₂CH₂OH and—CH₂CH(OH)CH₂OH.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(◯); —(CH₂)₀₋₄OR^(◯); —O(CH₂)₀₋₄R^(◯), —O—(CH₂)₀₋₄C(O)OR^(◯);—(CH₂)₀₋₄C H(OR^(◯))₂; —(CH₂)₀₋₄SR^(◯); —(CH₂)₀₋₄Ph, which may besubstituted with R^(◯); —(CH₂)₀₋₄O(CH₂)₀₋₄Ph which may be substitutedwith R^(◯); —CH═CHPh, which may be substituted with R^(◯);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(◯); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(◯))₂; —(CH₂)₀₋₄N(R^(◯))C(O)R^(◯);—N(R^(◯))C(S)R^(◯); —(CH₂)₀₋₄N(R^(◯))C(O)NR^(◯) ₂, —N(R^(◯))C(S)NR^(◯)₂; —(CH₂)₀₋₄N(R^(◯))C(O)OR^(◯); —N(R^(◯))N(R^(◯))C(O)R^(◯);—N(R^(◯))N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))N(R^(◯))C(O)OR^(◯);—(CH₂)₀₋₄C(O)R^(◯); —C(S)R^(◯); —(CH₂)₀₋₄C (O)OR^(◯);—(CH₂)₀₋₄C(O)SR^(◯); —(CH₂)₀₋₄C(O)OSiR^(◯) ₃; —(CH₂)₀₋₄OC(O)R^(◯);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(◯); —(CH₂)₀₋₄SC(O)R^(◯); —(CH₂)₀₋₄C(O)NR^(◯)₂; —C(S)NR^(◯) ₂; —C(S)SR^(◯); —SC(S)SR^(◯), —(CH₂)₀₋₄OC(O)NR^(◯) ₂;—C(O)N(OR^(◯))R^(◯); —C(O)C(O)R^(◯); —C(O)CH₂C(O)R^(◯);—C(NOR^(◯))R^(◯); —(CH₂)₀₋₄SSR^(◯); —(CH₂)₀₋₄S(O)₂R^(◯);—(CH₂)₀₋₄S(O)₂OR^(◯); —(CH₂)₀₋₄OS(O)₂R^(◯); —S(O)₂NR^(◯) ₂;—(CH₂)₀₋₄S(O)R^(◯); —N(R^(◯))S(O)₂NR^(◯) ₂; —N(R^(◯))S(O)₂R^(◯);—N(OR^(◯))R^(◯); —C(NH)NR^(◯) ₂; —P(O)₂R^(◯); —P(O)R^(◯) ₂; —OP(O)R^(◯)₂; —OP(O)(OR^(◯))₂; SiR^(◯) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(◯))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(◯))₂, wherein each R^(◯) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(◯), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(◯) (or the ring formed by takingtwo independent occurrences of R^(◯) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(), -(haloR^()),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(), —(CH₂)₀₋₂CH(OR^())₂; —O(haloR^()), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(),—(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(),—(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃, —OSi R^() ₃, —C(O)SR^(), —(C₁₋₄straight or branched alkylene)C(O)OR^(), or —SSR^() wherein each R^()is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(◯) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN, —C(O)OH,—C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein each R^() isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carrierand/or diluent and a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptablediluent” means non-therapeutic components that are of sufficient purityand quality for use in the formulation of a composition of the inventionthat, when appropriately administered to an animal or human, typicallydo not produce an adverse reaction, and that are used as a vehicle for adrug substance (i.e., a compound of the present invention).

Pharmaceutically acceptable salts of the compounds of the presentinvention are also included. For example, an acid salt of a compound ofthe present invention containing an amine or other basic group can beobtained by reacting the compound with a suitable organic or inorganicacid, resulting in pharmaceutically acceptable anionic salt forms.Examples of anionic salts include the acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glyceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, and triethiodide salts.

Salts of the compounds of the present invention containing a carboxylicacid or other acidic functional group can be prepared by reacting with asuitable base. Such a pharmaceutically acceptable salt may be made witha base which affords a pharmaceutically acceptable cation, whichincludes alkali metal salts (especially sodium and potassium), alkalineearth metal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, quinine, quinoline, and basicamino acids such as lysine and arginine.

The invention also includes various isomers and mixtures thereof.Certain of the compounds of the present invention may exist in variousstereoisomeric forms. Stereoisomers are compounds which differ only intheir spatial arrangement. Enantiomers are pairs of stereoisomers whosemirror images are not superimposable, most commonly because they containan asymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat are not related as mirror images, most commonly because theycontain two or more asymmetrically substituted carbon atoms. “R” and “S”represent the configuration of substituents around one or more chiralcarbon atoms. When a chiral center is not defined as R or S, either apure enantiomer or a mixture of both configurations is present.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to the other stereoisomers.When a single enantiomer is named or depicted by structure, the depictedor named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight optically pure. Percent optical purity by weight is the ratio ofthe weight of the enantiomer that is present divided by the combinedweight of the enantiomer that is present and the weight of its opticalisomer.

“Cis” means on the same side. “Trans” means on opposite sides. Thedesignation “cis” is used when two substituents have an ““up-up” or a“down-down” relationship. The designation “trans” is used when twosubstituents have an “up-down” or “down-up” relationship. Typically, twosubstituents that are “cis” to one another are arranged on the same sideof a molecule. When the term “cis” is used with reference to a fused,saturated or partially saturated ring system, the term is intended toindicate that the two atoms attached to the common ring atoms are cissubstituents. For example,

are cis diastereomers of a moiety having the following structuralformula:

The present invention also provides a method of treating or preventing asubject with a tetracycline-responsive disease or disorder comprisingadministering to the subject an effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt thereof.

“Tetracycline-responsive disease or disorder” refers to a disease ordisorder that can be treated, prevented, or otherwise ameliorated by theadministration of a tetracycline compound of the present invention.Tetracycline-responsive disease or disorder includes infections, cancer,inflammatory disorders, autoimmune disease, arteriosclerosis, cornealulceration, emphysema, arthritis, osteoporosis, osteoarthritis, multiplesclerosis, osteosarcoma, osteomyelitis, bronchiectasis, chronicpulmonary obstructive disease, skin and eye diseases, periodontitis,osteoporosis, rheumatoid arthritis, ulcerative colitis, prostatitis,tumor growth and invasion, metastasis, diabetes, diabetic proteinuria,panbronchiolitis, aortic or vascular aneurysms, skin tissue wounds, dryeye, bone, cartilage degradation, malaria, senescence, diabetes,vascular stroke, neurodegenerative disorders, cardiac disease, juvenilediabetes, acute and chronic bronchitis, sinusitis, and respiratoryinfections, including the common cold, Wegener's granulomatosis;neutrophilic dermatoses and other inflammatory diseases such asdermatitis herpetiformis, leukocytoclastic vasculitis, bullous lupuserythematosus, pustular psoriasis, erythema elevatum diutinum; vitiligo,discoid lupus erythematosus; pyoderma gangrenosum, pustular psoriasis,blepharitis, or meibomianitis, Alzheimer's disease, degenerativemaculopathy; acute and chronic gastroenteritis and colitis; acute andchronic cystitis and urethritis; acute and chronic dermatitis; acute andchronic conjunctivitis, acute and chronic serositis, uremicpericarditis; acute and chronic cholecystis, cystic fibrosis, acute andchronic vaginitis, acute and chronic uveitis, drug reactions, insectbites, burns and sunburn, bone mass disorder, acute lung injury, chroniclung disorders, ischemia, stroke or ischemic stroke, skin wound, aorticor vascular aneurysm, diabetic retinopathy, hemorrhagic stroke,angiogenesis, and other states for which tetracycline compounds havebeen found to be active (see, for example, U.S. Pat. Nos. 5,789,395;5,834,450; 6,277,061 and 5,532,227, each of which is expresslyincorporated herein by reference).

In addition, a method to treat any disease or disease state that couldbenefit from modulating the expression and/or function of nitric oxide,metalloproteases, proinflammatory mediators and cytokines, reactiveoxygen species, components of the immune response, including chemotaxis,lymphocyte transformation, delayed hypersensitivity, antibodyproduction, phagocytosis, and oxidative metabolism of phagocytes. Amethod to treat any disease or disease state that could benefit frommodulating the expression and/or function of C-reactive protein,signaling pathways (e.g., FAK signaling pathway), and/or augment theexpression of COX-2 and PGE₂ production is covered. A method to treatany disease or disease state that could benefit from inhibition ofneovascularization is covered.

Compounds of the invention can be used to prevent or treat importantmammalian and veterinary diseases such as diarrhea, urinary tractinfections, infections of skin and skin structure including wounds,cellulitis, and abscesses, ear, nose and throat infections, mastitis andthe like. In addition, methods for treating neoplasms using tetracyclinecompounds of the invention are also included (van der Bozert et al.,Cancer Res., 48: 6686-6690 (1988)).

Infections that can be treated using compounds of the invention or apharmaceutically acceptable salt thereof include, but are not limitedto, skin infections, GI infections, urinary tract infections,genito-urinary infections, respiratory tract infections, sinusesinfections, middle ear infections, systemic infections, intra-abdominalinfections, pyelonephritis, pneumonia, bacterial vaginosis,streptococcal sore throat, chronic bacterial prostatitis, gynecologicaland pelvic infections, sexually transmitted bacterial diseases, ocularand otic infections, cholera, influenza, bronchitis, acne, psoriasis,rosacea, impetigo, malaria, sexually transmitted disease includingsyphilis and gonorrhea, Legionnaires' disease, Lyme disease, RockyMountain spotted fever, Q fever, typhus, bubonic plague, gas gangrene,hospital acquired infections, leptospirosis, whooping cough, anthrax andinfections caused by the agents responsible for lymphogranulomavenereum, inclusion conjunctivitis, or psittacosis. Infections can bebacterial, fungal, parasitic and viral infections (including those whichare resistant to other tetracycline compounds).

In one embodiment, the infection is a respiratory infection. In aparticular aspect, the respiratory infection is Community-AcquiredBacterial Pneumonia (CABP). In a more particular embodiment, therespiratory infection, for example, CABP is caused by a bacteriumselected from S. aureus, S. pneumoniae, S. pyogenes, H. influenza, M.catarrhalis and Legionella pneumophila.

In another embodiment, the infection is a skin infection. In aparticular aspect the skin infection is an acute bacterial skin and skinstructure infection (ABSSSI). In a more particular embodiment, the skininfection, for example ABSSSI is caused by a bacterium selected from S.aureus, CoNS, S. pyogenes, S. agalactiae, E. faecalis and E. faecium.

In one embodiment, the infection can be caused by a bacterium (e.g. ananaerobic or aerobic bacterium).

In another embodiment, the infection is caused by a Gram-positivebacterium. In a specific aspect of this embodiment, the infection iscaused by a Gram-positive bacterium selected from class Bacilli,including, but not limited to, Staphylococcus spp., Streptococcus spp.,Enterococcus spp., Bacillus spp., Listeria spp.; phylum Actinobacteria,including, but not limited to, Propionibacterium spp., Corynebacteriumspp., Nocardia spp., Actinobacteria spp., and class Clostridia,including, but not limited to, Clostridium spp.

In another embodiment, the infection is caused by a Gram-positivebacterium selected from S. aureus, CoNS, S. pneumoniae, S. pyogenes, S.agalactiae, E. faecalis and E. faecium.

In another embodiment, the infection is caused by a Gram-negativebacterium. In one aspect of this embodiment, the infection is caused bya phylum Proteobacteria (e.g., Betaproteobacteria andGammaproteobacteria), including Escherichia coli, Salmonella, Shigella,other Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter,Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella oralpha-proteobacteria such as Wolbachia. In another aspect, the infectionis caused by a Gram-negative bacterium selected from cyanobacteria,spirochaetes, green sulfur or green non-sulfur bacteria. In a specificaspect of this embodiment, the infection is caused by a Gram-negativebacteria selected from Enterobactericeae (e.g., E. coli, Klebsiellapneumoniae including those containing extended-spectrum β-lactamasesand/or carbapenemases), Bacteroidetes (e.g., Bacteroides fragilis),Vibrionaceae (Vibrio cholerae), Pasteurellaceae (e.g., Haemophilusinfluenzae), Pseudomonadaceae (e.g., Pseudomonas aeruginosa),Neisseriaceae (e.g. Neisseria meningitidis), Rickettsiae, Moraxellaceae(e.g., Moraxella catarrhalis), any species of Proteeae, Acinetobacterspp., Helicobacter spp., and Campylobacter spp. In a particularembodiment, the infection is caused by Gram-negative bacterium selectedfrom the group consisting of Enterobactericeae (e.g., E. coli,Klebsiella pneumoniae), Pseudomonas, and Acinetobacter spp. In anotherembodiment, the infection is caused by an organism selected from thegroup consisting of K. pneumoniae, Salmonella, E. hirae, A. baumanii, M.catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S.aureus, and E. faecalis.

In another embodiment, the infection is cause by a gram negativebacterium selected from H. influenza, M. catarrhalis and Legionellapneumophila.

In one embodiment, the infection is caused by an organism that growsintracellularly as part of its infection process.

In another embodiment, the infection is caused by an organism selectedfrom the group consisting of order Rickettsiales; phylum Chlamydiae;order Chlamydiales; Legionella spp.; class Mollicutes, including, butnot limited to, Mycoplasma spp. (e.g. Mycoplasma pneumoniae);Mycobacterium spp. (e.g. Mycobacterium tuberculosis); and phylumSpriochaetales (e.g. Borrelia spp. and Treponema spp.).

In another embodiment, the infection is caused by a Category ABiodefense organism as described athttp://www.bt.cdc.gov/agent/agentlist-category.asp, the entire teachingsof which are incorporated herein by reference. Examples of Category Aorganisms include, but are not limited to, Bacillus anthracis (anthrax),Yersinia pestis (plague), Clostridium botulinum (botulism) orFrancisella tularensis (tularemia). In another embodiment the infectionis a Bacillus anthracis infection. “Bacillus anthracis infection”includes any state, diseases, or disorders caused or which result fromexposure or alleged exposure to Bacillus anthracis or another member ofthe Bacillus cereus group of bacteria.

Additional infections that can be treated using compounds of theinvention or a pharmaceutically acceptable salt thereof include, but arenot limited to, anthrax, botulism, bubonic plague, and tularemia.

In another embodiment, the infection is caused by a Category BBiodefense organism as described athttp://www.bt.cdc.gov/agent/agentlist-category.asp, the entire teachingsof which are incorporated herein by reference. Examples of Category Borganisms include, but are not limited to, Brucella spp, Clostridiumperfringens, Salmonella spp., Escherichia coli O157:H7, Shigella spp.,Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci,Coxiella burnetii, Staphylococcal enterotoxin B, Rickettsia prowazekii,Vibrio cholerae, and Cryptosporidium parvum.

Additional infections that can be treated using compounds of theinvention or a pharmaceutically acceptable salt thereof include, but arenot limited to, Brucellosis, Clostridium perfringens, food-borneillnesses, Glanders, Melioidosis, Psittacosis, Q fever, and water-borneillnesses.

In yet another embodiment, the infection can be caused by one or morethan one organism described above. Examples of such infections include,but are not limited to, intra-abdominal infections (often a mixture of agram-negative species like E. coli and an anaerobe like B. fragilis),diabetic foot (various combinations of Streptococcus, Serratia,Staphylococcus and Enterococcus spp., anaerobes (S. E. Dowd, et al.,PloS one 2008; 3:e3326, the entire teachings of which are incorporatedherein by reference) and respiratory disease (especially in patientsthat have chronic infections like cystic fibrosis—e.g., S. aureus plusP. aeruginosa or H. influenzae, atypical pathogens), wounds andabscesses (various gram-negative and gram-positive bacteria, notablyMSSA/MRSA, coagulase-negative staphylococci, enterococci, Acinetobacter,P. aeruginosa, E. coli, B. fragilis), and bloodstream infections (13%were polymicrobial (H. Wisplinghoff, et al., Clin. Infect. Dis. 2004;39:311-317, the entire teachings of which are incorporated herein byreference)).

In one embodiment, the infection is caused by an organism resistant toone or more antibiotics.

In another embodiment, the infection is caused by an organism resistantto tetracycline or any member of first and second generation oftetracycline antibiotics (e.g., doxycycline or minocycline).

In another embodiment, the infection is caused by an organism resistantto methicillin.

In another embodiment, the infection is caused by an organism resistantto vancomycin.

In another embodiment, the infection is caused by an organism resistantto a quinolone or fluoroquinolone.

In another embodiment, the infection is caused by an organism resistantto tigecycline or any other tetracycline derivative. In a particularembodiment, the infection is caused by an organism resistant totigecycline.

In another embodiment, the infection is caused by an organism resistantto a 3-lactam or cephalosporin antibiotic or an organism resistant topenems or carbapenems.

In another embodiment, the infection is caused by an organism resistantto an antimicrobial peptide or a biosimilar therapeutic treatment.Antimicrobial peptides (also called host defense peptides) are anevolutionarily conserved component of the innate immune response and arefound among all classes of life. In this case, antimicrobial peptiderefers to any naturally occurring molecule or any semi/syntheticmolecule that are analogs of anionic peptides, linear cationic α-helicalpeptides, cationic peptides enriched for specific amino acids (i.e, richin proline, arginine, phenylalanine, glycine, tryptophan), and anionicand cationic peptides that contain cystein and form disulfide bonds.

In another embodiment, the infection is caused by an organism resistantto macrolides, lincosamides, streptogramin antibiotics, oxazolidinones,and pleuromutilins.

In another embodiment, the infection is caused by an organism resistantto PTK0796 (7-dimethylamino,9-(2,2-dimethyl-propyl)-aminomethylcycline).

In another embodiment, the infection is caused by a multidrug-resistantpathogen (having intermediate or full resistance to any two or moreantibiotics).

In a further embodiment, the tetracycline responsive disease or disorderis not a bacterial infection. In another embodiment, the tetracyclinecompounds of the invention are essentially non-antibacterial. Forexample, non-antibacterial compounds of the invention may have MICvalues greater than about 4 μg/ml (as measured by assays known in theart and/or the assay given in Example 151. In another embodiment, thetetracycline compounds of the invention have both antibacterial andnon-antibacterial effects.

Tetracycline responsive disease or disorder also includes diseases ordisorders associated with inflammatory process associated states (IPAS).The term “inflammatory process associated state” includes states inwhich inflammation or inflammatory factors (e.g., matrixmetalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins, plasmaproteins, cellular defense systems, cytokines, lipid metabolites,proteases, toxic radicals, adhesion molecules, etc.) are involved or arepresent in an area in aberrant amounts, e.g., in amounts which may beadvantageous to alter, e.g., to benefit the subject. The inflammatoryprocess is the response of living tissue to damage. The cause ofinflammation may be due to physical damage, chemical substances,micro-organisms, tissue necrosis, cancer or other agents. Acuteinflammation is short-lasting, lasting only a few days. If it is longerlasting however, then it may be referred to as chronic inflammation.

IPASs include inflammatory disorders. Inflammatory disorders aregenerally characterized by heat, redness, swelling, pain and loss offunction. Examples of causes of inflammatory disorders include, but arenot limited to, microbial infections (e.g., bacterial and fungalinfections), physical agents (e.g., burns, radiation, and trauma),chemical agents (e.g., toxins and caustic substances), tissue necrosisand various types of immunologic reactions.

Examples of inflammatory disorders can be treated using the compounds ofthe invention or a pharmaceutically acceptable salt thereof include, butare not limited to, osteoarthritis, rheumatoid arthritis, acute andchronic infections (bacterial and fungal, including diphtheria andpertussis); acute and chronic bronchitis, sinusitis, and upperrespiratory infections, including the common cold; acute and chronicgastroenteritis and colitis; inflammatory bowel disorder; acute andchronic cystitis and urethritis; vasculitis; sepsis; nephritis;pancreatitis; hepatitis; lupus; inflammatory skin disorders including,for example, eczema, dermatitis, psoriasis, pyoderma gangrenosum, acnerosacea, and acute and chronic dermatitis; acute and chronicconjunctivitis; acute and chronic serositis (pericarditis, peritonitis,synovitis, pleuritis and tendinitis); uremic pericarditis; acute andchronic cholecystis; acute and chronic vaginitis; acute and chronicuveitis; drug reactions; insect bites; burns (thermal, chemical, andelectrical); and sunburn.

IPASs also include matrix metalloproteinase associated states (MMPAS).MMPAS include states characterized by aberrant amounts of MMPs or MMPactivity. Examples of matrix metalloproteinase associated states(“MMPAS's”) can be treated using compounds of the invention or apharmaceutically acceptable salt thereof, include, but are not limitedto, arteriosclerosis, corneal ulceration, emphysema, osteoarthritis,multiple sclerosis (Liedtke et al., Ann. Neurol. 1998, 44: 35-46;Chandler et al., J. Neuroimmunol. 1997, 72: 155-71), osteosarcoma,osteomyelitis, bronchiectasis, chronic pulmonary obstructive disease,skin and eye diseases, periodontitis, osteoporosis, rheumatoidarthritis, ulcerative colitis, inflammatory disorders, tumor growth andinvasion (Stetler-Stevenson et al., Annu. Rev. Cell Biol. 1993, 9:541-73; Tryggvason et al., Biochim. Biophys. Acta 1987, 907: 191-217; Liet al., Mol. Carcillog. 1998, 22: 84-89)), metastasis, acute lunginjury, stroke, ischemia, diabetes, aortic or vascular aneurysms, skintissue wounds, dry eye, bone and cartilage degradation (Greenwald etal., Bone 1998, 22:33-38; Ryan et al., Curr. Op. Rheumatol. 1996, 8:238-247). Other MMPAS include those described in U.S. Pat. Nos.5,459,135; 5,321,017; 5,308,839; 5,258,371; 4,935,412; 4,704,383,4,666,897, and RE 34,656, incorporated herein by reference in theirentirety.

In a further embodiment, the IPAS includes disorders described in U.S.Pat. Nos. 5,929,055; and 5,532,227, incorporated herein by reference intheir entirety.

Tetracycline responsive disease or disorder also includes diseases ordisorders associated with NO associated states. The term “NO associatedstates” includes states which involve or are associated with nitricoxide (NO) or inducible nitric oxide synthase (iNOS). NO associatedstate includes states which are characterized by aberrant amounts of NOand/or iNOS. Preferably, the NO associated state can be treated byadministering tetracycline compounds of the invention. The disorders,diseases and states described in U.S. Pat. Nos. 6,231,894; 6,015,804;5,919,774; and 5,789,395 are also included as NO associated states. Theentire contents of each of these patents are hereby incorporated hereinby reference.

Examples of diseases or disorders associated with NO associated statescan be treated using the compounds of the present invention or apharmaceutically acceptable salt thereof include, but are not limitedto, malaria, senescence, diabetes, vascular stroke, neurodegenerativedisorders (Alzheimer's disease and Huntington's disease), cardiacdisease (reperfusion-associated injury following infarction), juvenilediabetes, inflammatory disorders, osteoarthritis, rheumatoid arthritis,acute, recurrent and chronic infections (bacterial, viral and fungal);acute and chronic bronchitis, sinusitis, and respiratory infections,including the common cold; acute and chronic gastroenteritis andcolitis; acute and chronic cystitis and urethritis; acute and chronicdermatitis; acute and chronic conjunctivitis; acute and chronicserositis (pericarditis, peritonitis, synovitis, pleuritis andtendonitis); uremic pericarditis; acute and chronic cholecystis; cysticfibrosis, acute and chronic vaginitis; acute and chronic uveitis; drugreactions; insect bites; burns (thermal, chemical, and electrical); andsunburn.

In another embodiment, the tetracycline responsive disease or disorderis cancer. Examples of cancers that can be treated using the compoundsof the invention or a pharmaceutically acceptable salt thereof includeall solid tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas.Adenocarcinomas are carcinomas derived from glandular tissue or in whichthe tumor cells form recognizable glandular structures. Sarcomas broadlyinclude tumors whose cells are embedded in a fibrillar or homogeneoussubstance like embryonic connective tissue. Examples of carcinomas whichmay be treated using the methods of the invention include, but are notlimited to, carcinomas of the prostate, breast, ovary, testis, lung,colon, and breast. The methods of the invention are not limited to thetreatment of these tumor types, but extend to any solid tumor derivedfrom any organ system. Examples of treatable cancers include, but arenot limited to, colon cancer, bladder cancer, breast cancer, melanoma,ovarian carcinoma, prostate carcinoma, lung cancer, and a variety ofother cancers as well. The methods of the invention also cause theinhibition of cancer growth in adenocarcinomas, such as, for example,those of the prostate, breast, kidney, ovary, testes, and colon. In oneembodiment, the cancers treated by methods of the invention includethose described in U.S. Pat. Nos. 6,100,248; 5,843,925; 5,837,696; or5,668,122, incorporated herein by reference in their entirety.

Alternatively, the tetracycline compounds may be useful for preventingor reducing the likelihood of cancer recurrence, for example, to treatresidual cancer following surgical resection or radiation therapy. Thetetracycline compounds useful according to the invention are especiallyadvantageous as they are substantially non-toxic compared to othercancer treatments.

In a further embodiment, the compounds of the invention are administeredin combination with standard cancer therapy, such as, but not limitedto, chemotherapy.

Examples of tetracycline responsive states can be treated using thecompounds of the invention or a pharmaceutically acceptable salt thereofalso include neurological disorders which include both neuropsychiatricand neurodegenerative disorders, but are not limited to, such asAlzheimer's disease, dementias related to Alzheimer's disease (such asPick's disease), Parkinson's and other Lewy diffuse body diseases,senile dementia, Huntington's disease, Gilles de la Tourette's syndrome,multiple sclerosis, amyotrophic lateral sclerosis (ALS), progressivesupranuclear palsy, epilepsy, and Creutzfeldt-Jakob disease; autonomicfunction disorders such as hypertension and sleep disorders, andneuropsychiatric disorders, such as depression, schizophrenia,schizoaffective disorder, Korsakoffs psychosis, mania, anxietydisorders, or phobic disorders; learning or memory disorders, e. g.,amnesia or age-related memory loss, attention deficit disorder,dysthymic disorder, major depressive disorder, mania,obsessive-compulsive disorder, psychoactive substance use disorders,anxiety, phobias, panic disorder, as well as bipolar affective disorder,e. g., severe bipolar affective (mood) disorder (BP-1), bipolaraffective neurological disorders, e. g., migraine and obesity.

Further neurological disorders include, for example, those listed in theAmerican Psychiatric Association's Diagnostic and Statistical manual ofMental Disorders (DSM), the most current version of which isincorporated herein by reference in its entirety.

In another embodiment, the tetracycline responsive disease or disorderis diabetes. Diabetes that can be treated using the compounds of theinvention or a pharmaceutically acceptable salt thereof include, but arenot limited to, juvenile diabetes, diabetes mellitus, diabetes type I,or diabetes type II. In a further embodiment, protein glycosylation isnot affected by the administration of the tetracycline compounds of theinvention. In another embodiment, the tetracycline compound of theinvention is administered in combination with standard diabetictherapies, such as, but not limited to insulin therapy.

In another embodiment, the tetracycline responsive disease or disorderis a bone mass disorder. Bone mass disorders that can be treated usingthe compounds of the invention or a pharmaceutically acceptable saltthereof include disorders where a subjects bones are disorders andstates where the formation, repair or remodeling of bone isadvantageous. For examples bone mass disorders include osteoporosis (e.g., a decrease in bone strength and density), bone fractures, boneformation associated with surgical procedures (e. g., facialreconstruction), osteogenesis imperfecta (brittle bone disease),hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis,myeloma bone disease, and the depletion of calcium in bone, such as thatwhich is related to primary hyperparathyroidism. Bone mass disordersinclude all states in which the formation, repair or remodeling of boneis advantageous to the subject as well as all other disorders associatedwith the bones or skeletal system of a subject which can be treated withthe tetracycline compounds of the invention. In a further embodiment,the bone mass disorders include those described in U.S. Pat. Nos.5,459,135; 5,231,017; 5,998,390; 5,770,588; RE 34,656; 5,308,839;4,925,833; 3,304,227; and 4,666,897, each of which is herebyincorporated herein by reference in its entirety.

In another embodiment, the tetracycline responsive disease or disorderis acute lung injury. Acute lung injuries that can be treated using thecompounds of the invention or a pharmaceutically acceptable salt thereofinclude adult respiratory distress syndrome (ARDS), post-pump syndrome(PPS), and trauma. Trauma includes any injury to living tissue caused byan extrinsic agent or event. Examples of trauma include, but are notlimited to, crush injuries, contact with a hard surface, or cutting orother damage to the lungs.

The tetracycline responsive disease or disorders of the invention alsoinclude chronic lung disorders. Examples of chronic lung disorders thatcan be treated using the compounds of the invention or apharmaceutically acceptable salt thereof include, but are not limited,to asthma, cystic fibrosis, chronic obstructive pulmonary disease(COPD), and emphysema. In a further embodiment, the acute and/or chroniclung disorders that can be treated using the compounds of the inventionor a pharmaceutically acceptable salt thereof include those described inU.S. Pat. Nos. 5,977,091; 6,043,231; 5,523,297; and 5,773,430, each ofwhich is hereby incorporated herein by reference in its entirety.

In yet another embodiment, the tetracycline responsive disease ordisorder is ischemia, stroke, or ischemic stroke.

In a further embodiment, the tetracycline compounds of the invention ora pharmaceutically acceptable salt thereof can be used to treat suchdisorders as described above and in U.S. Pat. Nos. 6,231,894; 5,773,430;5,919,775 and 5,789,395, incorporated herein by reference.

In still a further embodiment, the tetracycline compounds of theinvention or a pharmaceutically acceptable salt thereof can be used totreat pain, for example, inflammatory, nociceptive or neuropathic pain.The pain can be either acute or chronic.

In another embodiment, the tetracycline responsive disease or disorderis a skin wound. The invention also provides a method for improving thehealing response of the epithelialized tissue (e.g., skin, mucosae) toacute traumatic injury (e.g., cut, burn, scrape, etc.). The methodincludes using a tetracycline compound of the invention or apharmaceutically acceptable salt thereof to improve the capacity of theepithelialized tissue to heal acute wounds. The method may increase therate of collagen accumulation of the healing tissue. The method may alsodecrease the proteolytic activity in the epithelialized tissue bydecreasing the collagenolytic and/or gellatinolytic activity of MMPs. Ina further embodiment, the tetracycline compound of the invention or apharmaceutically acceptable salt thereof is administered to the surfaceof the skin (e. g., topically). In a further embodiment, thetetracycline compound of the invention or a pharmaceutically acceptablesalt thereof is used to treat a skin wound, and other such disorders asdescribed in, for example, U.S. Pat. Nos. 5,827,840; 4,704,383;4,935,412; 5,258,371; 5,308,839, 5,459,135; 5,532,227; and 6,015,804;each of which is incorporated herein by reference in its entirety.

In yet another embodiment, the tetracycline responsive disease ordisorder is an aortic or vascular aneurysm in vascular tissue of asubject (e.g., a subject having or at risk of having an aortic orvascular aneurysm, etc.). The tetracycline compound or apharmaceutically acceptable salt thereof may be effective to reduce thesize of the vascular aneurysm or it may be administered to the subjectprior to the onset of the vascular aneurysm such that the aneurysm isprevented. In one embodiment, the vascular tissue is an artery, e.g.,the aorta, e.g., the abdominal aorta. In a further embodiment, thetetracycline compounds of the invention are used to treat disordersdescribed in U.S. Pat. Nos. 6,043,225 and 5,834,449, incorporated hereinby reference in their entirety.

The compounds of the invention or a pharmaceutically acceptable saltthereof can be used alone or in combination with one or more therapeuticagent in the methods of the invention disclosed herein.

The language “in combination with” another therapeutic agent ortreatment includes co-administration of the tetracycline compound andwith the other therapeutic agent or treatment as either a singlecombination dosage form or as multiple, separate dosage forms,administration of the tetracycline compound first, followed by the othertherapeutic agent or treatment and administration of the othertherapeutic agent or treatment first, followed by the tetracyclinecompound.

The other therapeutic agent may be any agent that is known in the art totreat, prevent, or reduce the symptoms of a tetracycline-responsivedisease or disorder. The choice of additional therapeutic agent(s) isbased upon the particular tetracycline-responsive disease or disorderbeing treated. Such choice is within the knowledge of a treatingphysician. Furthermore, the other therapeutic agent may be any agent ofbenefit to the patient when administered in combination with theadministration of a tetracycline compound.

The compounds of the invention or a pharmaceutically acceptable saltthereof can be used alone or in combination with one or more antibioticsand/or immunomodulators (e.g. Deoxycholic acid, Macrokine, Abatacept,Belatacept, Infliximab, Adalimumab, Certolizumab pegol, Afelimomab,Golimumab, and FKBP/Cyclophilin/Calcineurin: Tacrolimus, Ciclosporin,Pimecrolimus).

As used herein, the term “subject” means a mammal in need of treatmentor prevention, e.g., companion animals (e.g., dogs, cats, and the like),farm animals (e.g., cows, pigs, horses, sheep, goats and the like) andlaboratory animals (e.g., rats, mice, guinea pigs and the like).Typically, the subject is a human in need of the specified treatment.

As used herein, the term “treating” or ‘treatment” refers to obtainingdesired pharmacological and/or physiological effect. The effect caninclude achieving, partially or substantially, one or more of thefollowing results: partially or totally reducing the extent of thedisease, disorder or syndrome; ameliorating or improving a clinicalsymptom or indicator associated with the disorder; delaying, inhibitingor decreasing the likelihood of the progression of the disease, disorderor syndrome.

As used herein, “preventing” or “prevention” refers to reducing thelikelihood of the onset or development of disease, disorder or syndrome.

“Effective amount” means that amount of active compound agent thatelicits the desired biological response in a subject. In one embodiment,the effective amount of a compound of the invention is from about 0.01mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100mg/kg/day, or from about 0.5 mg/kg/day to about 50 mg/kg/day.

The invention further includes the process for making the compositioncomprising mixing one or more of the present compounds and an optionalpharmaceutically acceptable carrier; and includes those compositionsresulting from such a process, which process includes conventionalpharmaceutical techniques.

The compositions of the invention include ocular, oral, nasal,transdermal, topical with or without occlusion, intravenous (both bolusand infusion), inhalable, and injection (intraperitoneally,subcutaneously, intramuscularly, intratumorally, or parenterally)formulations. The composition may be in a dosage unit such as a tablet,pill, capsule, powder, granule, liposome, ion exchange resin, sterileocular solution, or ocular delivery device (such as a contact lens andthe like facilitating immediate release, timed release, or sustainedrelease), parenteral solution or suspension, metered aerosol or liquidspray, drop, ampoule, auto-injector device, or suppository; foradministration ocularly, orally, intranasally, sublingually,parenterally, or rectally, or by inhalation or insufflation.

Compositions of the invention suitable for oral administration includesolid forms such as pills, tablets, caplets, capsules (each includingimmediate release, timed release, and sustained release formulations),granules and powders; and, liquid forms such as solutions, syrups,elixirs, emulsions, and suspensions. Forms useful for ocularadministration include sterile solutions or ocular delivery devices.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

The compositions of the invention may be administered in a form suitablefor once-weekly or once-monthly administration. For example, aninsoluble salt of the active compound may be adapted to provide a depotpreparation for intramuscular injection (e.g., a decanoate salt) or toprovide a solution for ophthalmic administration.

The dosage form containing the composition of the invention contains aneffective amount of the active ingredient necessary to provide atherapeutic effect. The composition may contain from about 5,000 mg toabout 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of acompound of the invention or salt form thereof and may be constitutedinto any form suitable for the selected mode of administration. Thecomposition may be administered about 1 to about 5 times per day. Dailyadministration or post-periodic dosing may be employed.

For oral administration, the composition is preferably in the form of atablet or capsule containing, e.g., 500 to 0.5 milligrams of the activecompound. Dosages will vary depending on factors associated with theparticular patient being treated (e.g., age, weight, diet, and time ofadministration), the severity of the condition being treated, thecompound being employed, the mode of administration, and the strength ofthe preparation.

The oral composition is preferably formulated as a homogeneouscomposition, wherein the active ingredient is dispersed evenlythroughout the mixture, which may be readily subdivided into dosageunits containing equal amounts of a compound of the invention.Preferably, the compositions are prepared by mixing a compound of theinvention (or pharmaceutically acceptable salt thereof) with one or moreoptionally present pharmaceutical carriers (such as a starch, sugar,diluent, granulating agent, lubricant, glidant, binding agent, anddisintegrating agent), one or more optionally present inertpharmaceutical excipients (such as water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, and syrup), one ormore optionally present conventional tableting ingredients (such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesiumstearate, dicalcium phosphate, and any of a variety of gums), and anoptional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose andbeta-lactose), corn sweeteners and natural and synthetic gums (e.g.,acacia and tragacanth). Disintegrating agents include starch, methylcellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form.Tablets may be sugarcoated or filmcoated using standard techniques.Tablets may also be coated or otherwise compounded to provide aprolonged, control-release therapeutic effect. The dosage form maycomprise an inner dosage and an outer dosage component, wherein theouter component is in the form of an envelope over the inner component.The two components may further be separated by a layer which resistsdisintegration in the stomach (such as an enteric layer) and permits theinner component to pass intact into the duodenum or a layer which delaysor sustains release. A variety of enteric and non-enteric layer orcoating materials (such as polymeric acids, shellacs, acetyl alcohol,and cellulose acetate or combinations thereof) may be used.

Compounds of the invention may also be administered via a slow releasecomposition; wherein the composition includes a compound of theinvention and a biodegradable slow release carrier (e.g., a polymericcarrier) or a pharmaceutically acceptable non-biodegradable slow releasecarrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well knownin the art. Biodegradable carriers are used to form particles ormatrices which retain an active agent(s) and which slowlydegrade/dissolve in a suitable environment (e.g., aqueous, acidic, basicand the like) to release the agent. Such particles degrade/dissolve inbody fluids to release the active compound(s) therein. The particles arepreferably nanoparticles or nanoemulsions (e.g., in the range of about 1to 500 nm in diameter, preferably about 50-200 nm in diameter, and mostpreferably about 100 nm in diameter). In a process for preparing a slowrelease composition, a slow release carrier and a compound of theinvention are first dissolved or dispersed in an organic solvent. Theresulting mixture is added into an aqueous solution containing anoptional surface-active agent(s) to produce an emulsion. The organicsolvent is then evaporated from the emulsion to provide a colloidalsuspension of particles containing the slow release carrier and thecompound of the invention.

The compound disclosed herein may be incorporated for administrationorally or by injection in a liquid form such as aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, flavored emulsionswith edible oils such as cottonseed oil, sesame oil, coconut oil orpeanut oil and the like, or in elixirs or similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions, include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also includesynthetic and natural gums. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations, whichgenerally contain suitable preservatives, are employed when intravenousadministration is desired.

The compounds may be administered parenterally via injection. Aparenteral formulation may consist of the active ingredient dissolved inor mixed with an appropriate inert liquid carrier. Acceptable liquidcarriers usually comprise aqueous solvents and other optionalingredients for aiding solubility or preservation. Such aqueous solventsinclude sterile water, Ringer's solution, or an isotonic aqueous salinesolution. Other optional ingredients include vegetable oils (such aspeanut oil, cottonseed oil, and sesame oil), and organic solvents (suchas solketal, glycerol, and formyl). A sterile, non-volatile oil may beemployed as a solvent or suspending agent. The parenteral formulation isprepared by dissolving or suspending the active ingredient in the liquidcarrier whereby the final dosage unit contains from 0.005 to 10% byweight of the active ingredient. Other additives include preservatives,isotonizers, solubilizers, stabilizers, and pain-soothing agents.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed.

Compounds of the invention may be administered intranasally using asuitable intranasal vehicle.

In another embodiment, the compounds of this invention may beadministered directly to the lungs by inhalation.

Compounds of the invention may also be administered topically orenhanced by using a suitable topical transdermal vehicle or atransdermal patch.

For ocular administration, the composition is preferably in the form ofan ophthalmic composition. The ophthalmic compositions are preferablyformulated as eye-drop formulations and filled in appropriate containersto facilitate administration to the eye, for example a dropper fittedwith a suitable pipette. Preferably, the compositions are sterile andaqueous based, using purified water. In addition to the compound of theinvention, an ophthalmic composition may contain one or more of: a) asurfactant such as a polyoxyethylene fatty acid ester; b) a thickeningagents such as cellulose, cellulose derivatives, carboxyvinyl polymers,polyvinyl polymers, and polyvinylpyrrolidones, typically at aconcentration n the range of about 0.05 to about 5.0% (wt/vol); c) (asan alternative to or in addition to storing the composition in acontainer containing nitrogen and optionally including a free oxygenabsorber such as Fe), an anti-oxidant such as butylated hydroxyanisol,ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at aconcentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at aconcentration of about 0.01 to 0.5% (wt/vol); and e) other excipientssuch as an isotonic agent, buffer, preservative, and/or pH-controllingagent. The pH of the ophthalmic composition is desirably within therange of 4 to 8.

In certain embodiments, the composition of this invention includes oneor more additional agents. The other therapeutic agent may be any agentthat is capable of treating, preventing or reducing the symptoms of atetracycline-responsive disease or disorder. Alternatively, the othertherapeutic agent may be any agent of benefit to a patient whenadministered in combination with the tetracycline compound in thisinvention.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

EXEMPLIFICATION

The following abbreviations are used in throughout the application.

Ac acetyl

aq aqueous

9-BBN 9-borabicyclo[3.3.1]nonane

BHT t-butyl hydroxyl toluene

Bn benzyl

Boc tert-butoxycarbonyl

Bu butyl

dba dibenzylideneacetone

DCE 1,2-dichloroethane

DCM dichloromethane

DEM diethoxymethane

DIBAL-H diisobutylaluminum hydride

DIEA diisopropylethylamine

DMAP 4-(dimethylamino)pyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone

DMSO dimethylsulfoxide

DPPB 1,4-bis(diphenylphosphinebutane)

ESI ESI ionization

Et ethyl

eq equivalent

h hour

HPLC high performance liquid chromatography

i iso

IBX 2-iodoxybenzoic acid

LDA lithium diisopropylamide

LHMDS lithium bis(trimethylsilyl)amide

MHz mega hertz

Ms methylsulfonyl

MS mass spectrometry

MTBE methyl t-butyl ether

m/z mass/charge ratio

MW molecular weight

NCS N-chlorosuccinimide

NDMBA 1,3-dimethylbarbituric acid

NMO N-methylmorpholine N-oxide

NMR nuclear magnetic resonance spectrometry

Ph phenyl

Pr propyl

s secondary

t tertiary

TBAF tetrabutylammonium fluoride

TEA triethylamine

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

TMEDA N,N,N′N′-tetramethylethylenediamine

TMP 2,2,6,6-tetramethylpiperidine

STAB sodium triacetoxyborohydride

The compounds described herein were synthesized in accordance with thefollowing Schemes. The specific approaches and compounds shown below arenot intended to be limiting. The chemical structures in the schemesherein depict variables that are hereby defined commensurately withchemical group definitions (moieties, atoms, etc.) of the correspondingposition in the compound formulae herein, whether identified by the samevariable name (i.e., R¹, R², R³, etc.) or not. The suitability of achemical group in a compound structure for use in the synthesis ofanother compound is within the knowledge of one of ordinary skill in theart.

Additional methods of synthesizing the compounds described herein andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene, T W et al., Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons (1999); Fieser, L et al.,Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons(1994); and Paquette, L, ed., Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons (1995) and subsequent editions thereof.

The following compounds were prepared according to Scheme 1.

To a mixture of aldehyde S1-1 (12.16 g, 43.11 mmol, 1.0 eq, preparedaccording to literature procedures including U.S. Pat. No. 7,763,3735),(S)-tert-butylsulfinamide (6.27 g, 51.73 mmol, 1.2 eq) and CuSO₄ (4.82g, 30.16 mmol, 0.7 eq) was added anhydrous toluene (85 mL) undernitrogen. The resulting reaction mixture was heated at 40° C. overnight,then cooled to rt and diluted with water (130 mL). The resulting mixturewas extracted with EtOAc (130 mL, then 2×30 mL). The combined organicphase was dried over Na₂SO₄, filtered and concentrated under reducedpressure. Flash chromatography on silica gel using 5%→15% EtOAc/hexanesyielded the desired product S1-2-2 as a thick yellow oil (15.29 g, 92%):¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 7.48-7.46 (m, 2H), 7.42-7.35 (m,3H), 5.37 (s, 2H), 1.26 (s, 9H); MS (ESI) m/z 385.02, 387.05 (M+H).

To a solution of ZnCl₂ (5.22 mL, 1.9M in MeTHF, 9.92 mmol, 0.25 eq) inTHF (75 mL) was added a solution of MeLi (6.61 mL, 3.0M in DEM, 19.84mmol, 0.5 eq) keeping the internal temperature below −58° C. Vinylmagnesium chloride solution (37.2 mL, 1.6M in THF, 59.53 mmol, 1.5 eq)was added at below −52° C. A solution of imine S1-2-2 (15.29 g, 39.68mmol, 1.0 eq) in THF (50 mL) was added dropwise via cannula keeping theinternal temperature below −76° C. over one hour. The resulting reactionsolution was stirred at −78° C. for an additional hour and quenched withcitric acid aqueous solution (8 g in 80 mL water) allowing the internaltemperature to rise to −3° C. The resulting mixture was extracted withEtOAc (150 mL, then 30 mL). The combined organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure. Flashchromatography on silica gel using 30%→38% EtOAc/hexanes yielded thedesired product S1-3-2 (15.46 g) as the major diastereomer: ¹H NMR (400MHz, CDCl₃) δ 7.45-7.43 (m, 2H), 7.40-7.34 (m, 3H), 5.96-5.88 (m, 1H),5.39 (d, J=17.7 Hz, 1H), 5.34 (d, J=9.8 Hz, 1H), 5.28 (s, 2H), 5.11 (t,J=6.7 Hz, 1H), 3.78 (d, J=6.1 Hz, 1H), 1.23 (s, 9H); MS (ESI) m/z413.05, 415.05 (M+H).

To a solution of compound S1-3-2 (15.46 g, 37.4 mmol, 1 eq) in methanol(122 mL) was added concentrated aqueous hydrochloric acid (6.23 mL, 74.8mmol, 2.0 eq). After 50 min at room temperature, consumption of startingmaterial was indicated by LC/MS. Solvent was evaporated and the residuewas partitioned between EtOAc (150 mL) and saturated aqueous NaHCO₃ (150mL). The organic phase was separated. The aqueous layer was furtherextracted with EtOAc (2×50 mL). The combined organic phase was washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford crude product S1-4-b: MS (ESI) m/z 309.07,311.04 (M+H), which was used directly for the next step.

To a mixture of the above intermediate S1-4-b, NaI (560 mg, 3.74 mmol,0.1 eq) and K₂CO₃ (12.9 g, 93.5 mmol, 2.5 eq) in THF (110 mL) was addedallyl bromide (14.6 mL, 168.3 mmol, 4.5 eq). The resulting reactionmixture was heated at 65° C. overnight. Then more allyl bromide (7 mL,80.7 mmol, 2.2 eq) was added. The resulting reaction mixture was heatedat 65° C. overnight and cooled to rt. The reaction mixture was dilutedwith EtOAc (300 mL), washed with water and brine. The organic phase wasthen dried over Na₂SO₄, filtered and concentrated under reducedpressure. Flash chromatography on silica gel using 1%→10% EtOAc/hexanesyielded the desired product S1-4-2 (11.32 g, 74% over 3 steps): ¹H NMR(400 MHz, CDCl₃) δ 7.47-7.45 (m, 2H), 7.41-7.34 (m, 3H), 6.02-5.94 (m,1H), 5.84-5.73 (m, 2H), 5.30 (s, 2H), 5.31-5.28 (m, 1H), 5.24-5.16 (m,3H), 5.14-5.11 (m, 2H), 4.60-4.59 (m, 1 H), 3.29 (dd, J=7.3, 14.6 Hz,2H), 3.04 (dd, J=6.7, 14.6 Hz, 2H); MS (ESI) m/z 389.16, 391.15 (M+H).

To a solution of bromide S1-4-2 (11.32 g, 29.08 mmol, 1 eq) in THF (110mL) was added Turbo Grignard solution (1.3M in THF, 26.8 mL, 34.89 mmol,1.2 eq) dropwise at ˜−10° C. The resulting reaction solution was stirredat that temperature for 30 min, and the cold bath was removed. Thereaction was warmed up to 0° C. and then cooled to −30° C. Then asolution of 3-methoxy-2-furaldehyde (4.40 g, 34.89 mmol, 1.2 eq) in THF(20 mL) was added over 10 min at −30° C. to −40° C. The resultingreaction mixture was stirred at −30° C. for 30 min and allowed to warmup to −15° C. Saturated aqueous NH₄Cl was added, and the resultingreaction mixture was extracted with EtOAc (120 mL, then 50 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. Flash chromatography on silica gel using 1%→20%EtOAc/hexanes yielded the desired product S1-5-2 (˜1:1 diastereomers):MS (ESI) m/z 437.25 (M+H).

Product S1-5-2 from the previous step was dissolved in 60 mL DMSO.Diisopropylethylamine (5.57 mL, 31.99 mmol, 1.1 eq) and BHT (˜100 mg,0.454 mmol, 0.016 eq) were added. The mixture was vacuumed and thenfilled with nitrogen. And this degas procedure was repeated four times.The reaction mixture was then stirred at 92° C. for 23 h to yieldintermediates S1-6-2. The reaction solution was cooled to roomtemperature. Ethyl acetate (120 mL) and triethyl amine (12.97 mL, 93.06mmol, 3.2 eq) were added. The reaction mixture was cooled to 0° C. TFAA(6.47 mL, 46.53 mmol, 1.6 eq) was added at 0 to 4° C. over 5 min. Afterstirring at 0° C. for 35 min, more TFAA (1.4 mL, 10.07 mmol, 0.35 eq)was added at 0 to 4° C. and the reaction was stirred at 0° C. foranother 30 min. Water (120 mL) was added to the reaction. After stirringfor 5 min the two layers were separated. The aqueous layer was extractedwith ethyl acetate (150 mL). The combined organic layers were washedwith water (150 mL) and brine (150 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel using 5%→50% EtOAc/hexanes to yield the desired product S1-7-2 (˜3:1diastereomers, 10.8 g, 86% over 3 steps) as a light brownish solid: MS(ESI) m/z 435.24 (M+H).

The above compound S1-7-2 was dissolved in DCM (70 mL), and theresulting solution was cooled to −30° C. A solution of BCl₃ in DCM (1M,29.83 mL, 29.83 mmol, 1.2 eq) was added at −20° C. to −30° C. Afterstirring for 40 min at the same temperature, more BCl₃ in DCM (1M, 0.5eq) was added at −20° C. to −30° C. After stirring for 30 min at thesame temperature, the reaction was quenched with aq. 20% K₃PO₄.7H₂O (100mL). The two layers were separated. The aqueous layer was extracted withDCM (30 mL). The combined organic layers were washed with brine (50 mL).The resulting organic layer was concentrated to −100 mL, and to whichwas added TFA (9.6 mL, 124.3 mmol, 5.0 eq). The resulting dark brownishreaction solution was stirred at room temperature for 1.5 h. Aq. 20%K₃PO₄ (250 mL) was added to adjust pH to −8. The two layers wereseparated. The aqueous layer was extracted with DCM (2×20 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give crude product S1-8-2: MS (ESI) m/z421.21 (M+H).

The crude product S1-8-2 from the previous step was dissolved in EtOAc(80 mL). The reaction solution was cooled with an ice/water bath.2,6-Lutidine (4.62 mL, 39.8 mmol, 1.6 eq) was added to the reactionmixture followed by TBSOTf (7.42 mL, 32.32 mmol, 1.3 eq). After stirringfor 15 min the cold bath was removed. The reaction mixture was stirredat room temperature for 50 min. The reaction was quenched with water.The organic layer was separated and washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel using 1%→10% EtOAc/hexanes to yield a lightorange solid, which was then stirred with hexanes (50 mL) overnight andfiltered. The filter cake was dried under high vacuum to give thedesired product S1-9-2 (7.07 g, 53% over 2 steps): ¹H NMR (400 MHz,CDCl₃) δ 7.46-7.44 (m, 2H), 7.36-7.29 (m, 3H), 6.87-6.83 (m, 1H),6.03-6.00 (m, 1H), 5.73-5.63 (m, 2H), 5.30 (s, 2H), 5.15 (d, J=17.1 Hz,2H), 5.10 (d, J=9.8 Hz, 2H), 4.05 (d, J=10.4 Hz, 1H), 3.24-3.17 (m, 4H),2.87-2.66 (m, 3H), 0.78 (s, 9H), 0.20 (s, 3H), 0.00 (s, 3H); MS (ESI)m/z 535.33 (M+H).

A mixture of the Pd(dba)₂ (98 mg, 0.171 mmol, 0.1 eq) and DPPB (73 mg,0.171 mmol, 0.1 eq) was dissolved in THF (1.5 mL). The resultingreaction solution was stirred at rt for 15 min, and added to a solutionof enone S1-9-2 (915 mg, 1.71 mmol, 1 eq) and 2-mercaptobenzoic acid(343 mg, 2.22 mmol, 1.3 eq) in THF (8 mL). The resulting orange reactionsolution was stirred at rt under nitrogen for 3 overnights. Thensaturated aq. NaHCO₃ was added. The resulting mixture was extracted withEtOAc (40 mL, then 20 mL). The combined organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Flash chromatography on silica gel using 1%→30% EtOAc/hexanesyielded the desired product S1-9-4 (196 mg, 23%) along with SM (138 mg,15%) and di-deallylation product (239 mg, 31%): ¹H NMR (400 MHz, CDCl₃)δ 7.50-7.46 (m, 2H), 7.38-7.32 (m, 3H), 6.84 (br s, 1H), 6.09 (dt,J=10.4, 1.8 Hz, 1H), 5.85-5.84 (br m, 1H), 5.35 (s, 2H), 5.25 (d, J=14.6Hz, 1H), 5.15 (d, J=11.0 Hz, 1H), 3.82 (br s, 1H), 3.55 (dd, J=5.5, 13.4Hz, 1H), 3.42 (br s, 1H), 2.78 (br s, 3H), 0.76 (s, 9H), 0.14 (s, 6H);MS (ESI) m/z 495.24 (M+H).

To a solution of compound S1-9-4 (196 mg, 0.396 mmol, 1 eq) in DCM (5mL) was added HCHO (37 wt % in water, 88 μL, 1.19 mmol, 3.0 eq), HOAc(34 μL, 0.594 mmol, 1.5 eq) and STAB (126 mg, 0.594 mmol, 1.5 eq). Theresulting reaction mixture was stirred at rt for 1 h, and more STAB (0.5eq) was added. The resulting reaction was stirred at rt overnight. Thensaturated aq. NaHCO₃ was added. The resulting mixture was extracted withDCM (20 mL, then 10 mL). The combined organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure. Flashchromatography on silica gel using 1%→10% EtOAc/hexanes yielded thedesired product S1-9-5 (155 mg, 77%) as a white foamy solid: ¹H NMR (400MHz, CDCl₃) δ 7.45-7.44 (m, 2H), 7.35-7.28 (m, 3H), 6.89-6.86 (m, 1H),6.03 (d, J=10.4 Hz, 1H), 5.73-5.63 (m, 1H), 5.30 (s, 2H), 5.17 (d,J=17.1 Hz, 1H), 5.10 (d, J=9.8 Hz, 1H), 3.89 (d, J=10.4 Hz, 1H),3.34-3.26 (m, 2H), 2.83-2.71 (m, 3H), 2.27 (s, 3H), 0.78 (s, 9H), 0.20(s, 3H), 0.00 (s, 3H); MS (ESI) m/z 509.24 (M+H).

To a solution of compound S1-3-2 (3.93 g, 9.51 mmol, 1 eq) in methanol(30 mL) was added concentrated aqueous hydrochloric acid (1.59 mL, 19.11mmol, 2.0 eq). The reaction was stirred at room temperature for 40 minto afford intermediate S1-4-b. The reaction solution was cooled to 0° C.NaOAc (2.44 g, 29.77 mmol, 3.13 eq), acetaldehyde (4.75 mL, 84.64 mmol,8.9 eq) and picoline-borane (2.00 g, 18.73 mmol, 1.97 eq) were added insequence. The resulting reaction mixture was stirred at rt for 1 h and30 min. Water (10 mL) was added and then the solvent was evaporated. Tothe residue was added concentrated aqueous hydrochloric acid (3.38 mL)and water (10 mL). The resulting solution was extracted with MTBE, andthe organic phase was discarded. To the aqueous layer was added toluene(40 mL) followed by aq. NaOH solution (6N, 7.9 mL) to make the aqueouslayer pH=˜9. The organic phase was separated, and the aqueous layer wasextracted with toluene (20 mL). The combined organic phase was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Flashchromatography on silica gel using 0%→25% EtOAc/hexanes yielded thedesired product S1-4-3 (3.09 g, 89%) as a colorless liquid: ¹H NMR (400MHz, CDCl₃) δ 7.46-7.44 (m, 2H), 7.40-7.32 (m, 3H), 6.05-5.97 (m, 1H),5.29 (s, 2H), 5.29-5.21 (m, 2H), 4.52 (d, J=6.7 Hz, 1H), 2.73-2.64 (m,2H), 2.54-2.46 (m, 2H), 1.02 (t, J=6.7 Hz, 6H); MS (ESI) m/z 365.17,367.17 (M+H).

Compound S1-9-3 was prepared using the same synthetic sequence (additionto furaldehyde, Diels-Alder, oxidation, BCl₃ oxo-bridge opening and TBSprotection) for compound S1-9-2 from isoxazole S1-4-3 (3.09 g) in 42%overall yield: ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.43 (m, 2H), 7.34-7.27(m, 3H), 6.90-6.86 (m, 1H), 6.05 (dd, J=3.0, 10.4 Hz, 1H), 5.28 (s, 2H),3.89 (d, J=10.4 Hz, 1H), 2.91-2.56 (m, 7H), 0.97 (t, J=7.3 Hz, 6H), 0.78(s, 9H), 0.21 (s, 3H), 0.00 (s, 3H); MS (ESI) m/z 511.34 (M+H).

To a solution of ZnCl₂ (12.13 mL, 1.85M in MeTHF, 22.44 mmol, 0.275 eq)in THF (125 mL) was added a solution of MeLi (13.6 mL, 3.0M in DEM,40.80 mmol, 0.5 eq) keeping the internal temperature below −55° C. Vinylmagnesium chloride solution (76.5 mL, 1.6M in THF, 122.4 mmol, 1.5 eq)was added at below −61° C. A solution of imine S1-2-1 (25 g, 81.60 mmol,1.0 eq, prepared from S1-1-1 by similar procedures used for S1-2-2) inTHF (75 mL) was added dropwise via cannula keeping the internaltemperature below −74° C. over 1 h and 20 min. The resulting reactionsolution was stirred at −78° C. for an additional 35 min and quenchedwith citric acid aqueous solution (12.5 g in 125 mL water) allowing theinternal temperature to rise to −35° C. The resulting mixture was warmedup to rt and extracted with EtOAc (200 mL). The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the desired product S1-3-1 (dr=˜99.3:0.7) inquantitative yield as a light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ7.42-7.33 (m, 5H), 5.96-5.87 (m, 1H), 5.92 (s, 1H), 5.43 (d, J=17.1 Hz,1H), 5.37 (d, J=11.0 Hz, 1H), 5.22 (s, 2H), 5.03 (dt, J=1.2, 6.1 Hz,1H), 3.77 (d, J=4.3 Hz, 1H), 1.23 (s, 9H); MS (ESI) m/z 335.20 (M+H).

To a solution of the above crude material S1-3-1 in methanol (200 mL)was added concentrated aqueous hydrochloric acid (13.7 mL, 164 mmol,2.01 eq) at 10 to 15° C. The reaction as stirred at room temperature for1 h to afford the primary amine intermediate S1-4-a. The reactionsolution was cooled to 0° C. Then NaOAc (20.08 g, 244.8 mmol, 3.0 eq)and picoline-borane (8.37 g, 81.60 mmol, 1 eq) were added in sequence.Then a solution of acetaldehyde in EtOH (50 wt %, 8.15 mL, 81.60 mmol,1.0 eq) was added dropwise. The resulting reaction mixture was stirredat 0° C. for 1 h and 50 min. An aqueous hydrochloric acid solution (1N,280 mL) was added and then the solvent was evaporated. To the residuewas added aqueous hydrochloric acid (1N, 50 mL). The resulting solutionwas extracted with MTBE (400 mL), and the organic phase was discarded.The aqueous layer was basified with aq. NaOH solution (6N, 58 mL) topH=˜8. The resulting mixture was extracted with toluene (300 mL, then150 mL). The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Flash chromatography on silica gelusing 5%→30% EtOAc/hexanes yielded the desired mono-ethylamineintermediate (15.24 g, 72% over 2 steps) as a yellow oil: ¹H NMR (400MHz, CDCl₃) δ 7.43-7.31 (m, 5H), 5.91-5.82 (m, 1H), 5.79 (s, 1H),5.31-5.22 (m, 2H), 5.22 (s, 2H), 4.29 (d, J=6.7 Hz, 1H), 2.69-2.56 (m,2H), 1.10 (t, J=7.0 Hz, 3H); MS (ESI) m/z 259.14 (M+H).

To a solution of the above mono-ethyl amine (15.24 g, 59.0 mmol, 1 eq)in MeCN (90 mL) was added HCHO (13.2 mL, 177 mmol, 3 eq) at 0° C.,followed by HOAc (6.75 mL, 118 mmol, 2 eq) and sodiumtriacetoxyborohydride (15.0 g, 70.8 mmol, 1.2 eq). The resultingreaction mixture was stirred at rt for 30 min, and quenched by slowaddition of saturated aqueous sodium bicarbonate (320 mL). The resultingmixture was stirred at rt for 10 min, and extracted with EtOAc (150 mL,then 100 mL). The organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated. Flash chromatography on silica gel using10%→25% EtOAc/hexanes yielded the desired product S1-4-1 (15.89 g, 99%)as a pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.33 (m, 5H),5.98-5.89 (m, 1H), 5.78 (s, 1H), 5.30-5.24 (m, 2H), 5.24 (s, 2H), 4.20(d, J=7.3 Hz, 1H), 2.51-2.40 (m, 2H), 2.22 (s, 3H), 1.05 (t, J=7.3 Hz,3H); MS (ESI) m/z 273.15 (M+H).

To a solution of isoxazole S1-4-1 (14.88 g, 54.64 mmol, 1 eq) in DME(29.8 mL) was added a solution of TMPMgCl.LiCl in THF (0.97M, 81.67 mL,79.22 mmol, 1.45 eq) at −5° C. to −2° C. over 10 min. The resultingreaction solution was stirred at 0° C. for 1 h, and then cooled to −78°C. A solution of furaldehyde (10.34 g, 81.96 mmol, 1.5 eq) in THF (65mL) was added dropwise to the reaction mixture via cannula at below −71°C. over 25 min. The resulting reaction mixture was allowed to warm up to−17° C. over 3.5 h, and quenched with saturated NH₄Cl (300 mL). Theresulting mixture was extracted with ethyl acetate (350 mL). The organicphase was separated, washed with saturated NH₄Cl (2×150 mL) and brine(100 mL), dried over Na₂SO₄, filtered and concentrated. The crudeproduct S1-5-1 (˜1:1 diastereomers) was used directly for the nextreaction without further purification.

Compound S1-9-1 was prepared using the same synthetic sequence(Diels-Alder, oxidation, BCl₃ oxo-bridge opening and TBS protection) forcompound S1-9-2 from the crude addition product S1-5-1 in 26% yield over5 steps: ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.43 (m, 2H), 7.35-7.28 (m, 3H),6.90-6.87 (m, 1H), 6.06-6.03 (m, 1H), 5.29 (s, 2H), 3.81 (d, J=11.0 Hz,1H), 2.84-2.63 (m, 5H), 2.28 (s, 3H), 1.01 (t, J=7.3 Hz, 3H), 0.78 (s,9H), 0.20 (s, 3H), 0.00 (s, 3H); MS (ESI) m/z 497.18 (M+H).

The following compounds were prepared according to Scheme 2.

Azetidine (8.31 g, 88.82 mmol, HCl salt) and sodium hydroxide (3.375 g,84.38 mmol) were mixed in 25 mL ethanol cooling with an ice water bath.The mixture was stirred at room temperature overnight and then dilutedwith 10 mL dichloromethane. In another flask, allylic alcohol 1 (3.42 g,14.8 mmol, 1.0 eq) and triethylamine (1.94 g, 19.24 mmol, 1.3 eq) wasdissolved in dichloromethane (34 mL). The solution was cooled to −20 to−15° C. At this temperature MsCl (2.03 g, 17.76 mmol, 1.2 eq) was added.After addition the reaction mixture was stirred at the same temperaturefor 0.5 h. The above azetidine free base (6 eq) was added to thereaction mixture at −20° C. in 20 min. After the addition, the reactionmixture was placed in a freezer over the weekend. Water (100 mL) wasadded. The mixture was filtered through a pad of Celite. The organiclayer was separated and concentrated to give 5 g crude product. Thecrude was dissolved in 35 ml of ethyl acetate. The ethyl acetatedsolution was extracted with aqueous hydrochloric acid (1N, 20 mL and0.5N, 10 mL). The combined aqueous solution was washed with 10 mL ofMTBE and then basified with aqueous sodium hydroxide (2N, 15 mL). Themixture was extracted with MTBE (30 mL and 20 mL). The combined organicswere washed with water and brine, and concentrated to give 2.2 g ofproduct. This product was loaded on a 10 g silica gel column, elutedwith hexane and ethyl acetate (2:1, 150 mL) to give 1.6 g of product2-2-1: ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.30 (m, 5H), 5.78 (s, 1H),5.75-5.66 (m, 1H), 5.29 (d, J=17.1 Hz, 1H), 5.23 (d, J=8.72 Hz, 1H),5.22 (s, 2H), 3.85 (d, J=8.24 Hz, 1H), 3.21 (m, 4H), 2.06 (m, 2H); MS(ESI) m/z 271.1 (M+H).

Compound 2-2-1 (1.6 g, 5.93 mmol) was dissolved in 16 mL of THF, cooledto −100° C. using a liquid nitrogen/ethanol bath. A solution of n-BuLi(2.5M, 2.84 mL, 7.11 mmol, 1.2 eq) was added at −101° C. to −99° C. togive a golden colored solution. The solution was gradually warmed up to−64° C. The then purple colored solution was cooled to −70° C. Asolution of 3-methoxy-2-furaldehyde (0.90 g, 7.11 mmol, 1.2 eq) in 3.5mL THF was added to the reaction mixture at below −62° C. After additionthe reaction mixture was gradually warmed up to −5° C. The reaction wasquenched with 20 mL of saturated ammonium chloride solution andextracted with MTBE (30 mL and 20 mL). The combined organics were washedwith brine and concentrated to give 2.5 g of crude product. The crudewas loaded on a 8 g silica gel column and eluted with hexane and ethylacetate (5:1) to give 1.8 g of S2-3-1 as a mixture of two diastereomersas (thick oil).

Compound 2-3-1 (2.5 g, 6.31 mmol) was dissolved in 30 mL of dioxane. Tothe solution was added diisopropylethylamine (0.90 g, 6.94 mmol, 1.1 eq)and BHT (25 mg). The reaction mixture was stirred at 95° C. for 1 week.The mixture was evaporated to dryness to give 1.94 g of crude productS2-4-1 as a mixture of 4 diastereomers. The crude was directly used inthe next step.

Compound 2-4-1 (1.94 g, 4.90 mmol) was dissolved in 20 mL ofdichloromethane. To the solution was added DMSO (1.53 g, 19.6 mmol, 4.0eq) and triethylamine (1.98 g, 19.6 mmol, 4.0 eq). The mixture wascooled with an ice water cooling bath. Sulfur trioxide pyridine complex(1.95 g, 12.25 mmol, 2.5 eq) was added. After addition the cooling bathwas removed and the reaction mixture was stirred at rt for 2 h.Additional 0.3 g of sulfur trioxide pyridine complex was added. Afterstirring for another 0.5 h the reaction mixture was cooled with an icewater cooling bath and quenched with water. The organic layer wasseparated, washed with water and brine, and concentrated to give 1.05 gof compound S2-5-1 as a mixture of 2 diastereomers: MS (ESI) m/z 395.1(M+H).

Compound 2-5-1 (1.0 g, 2.54 mmol) was dissolved in 20 mL ofdichloromethane. The solution was cooled. A 1M solution of BCl₃ indichloromethane (3.81 mL, 3.81 mmol, 1.5 eq) was added at −13° C. to−15° C. After addition the reaction mixture was stirred at the sametemperature for 20 min and then quenched with 20 mL 20% aqueouspotassium phosphate tribasic solution. The two layers were separated.The aqueous layer was extracted with 10 mL of dichloromethane. Thecombined organics were washed with brine and concentrated to give 0.7 gof crude product S2-6-1 (mixture of two diastereomers) as a brown oil:MS (ESI) m/z 381.1 (M+H).

Compound S2-6-1 (0.7 g, 1.84 mmol) was dissolved in 10 mLdichloromethane. The solution was cooled with an ice water bath. To thesolution was added 2,6-lutidine (0.34 mL, 2.94 mmol, 1.6 eq) followed byTBSOTf (0.55 mL, 2.39 mmol, 1.3 eq). The reaction was stirred with icewater cooling for 1 h and then quenched with 10 mL of water. The organiclayer was separated, washed with brine and concentrated to give 1 g ofcrude product. The crude was loaded on a 20 g silica gel column, elutedwith hexane and ethyl acetate (6 to 1, 280 mL) to give 140 mg productS2-7-1 as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.42 (m, 2H),7.36-7.26 (m, 3H), 6.91-6.83 (m, 1H), 6.04-5.99 (m, 1H), 5.32 (s, 2H)3.66-3.56 (m, 3H), 3.30-3.22 (m, 2H), 2.88-2.70 (m, 2H), 2.44-2.38 (m,1H), 2.12-2.04 (m, 2H), 0.77 (s, 9H), 0.22 (s, 3H), 0.00 (s, 3H); MS(ESI) m/z 495.2 (M+H).

Compound S2-1 (10 g, 43.3 mmol, 1.0 eq) and triethylamine (7.85 mL, 56.3mmol, 1.3 eq) were mixed in 150 mL of dichloromethane. The solution wascooled to −27° C. Neat MsCl (3.85 mL, 49.8 mmol, 1.15 eq) was added tothe reaction mixture dropwise maintaining the temperature below −20° C.After stirring for additional 30 min, the reaction mixture was furthercooled and 2,2,2-trifluoroethanol (24 mL) was added at below −32° C.Pyrrolidine (22.4 mL, 259.8 mmol, 6.0 eq) was added dropwise maintainingtemperature at −32° C. to −25° C. After addition the reaction mixturewas stirred for 15 min and then stored in a freezer (−23° C.) overnight.Water (100 mL) was added to quench the reaction. The two layers wereseparated. The organic layer was concentrated to dryness. The residuewas dissolved in 200 mL of MTBE. After washing with 100 mL of water 3times, the MTBE solution was cooled with an ice/water bath. Aqueous HCl(1M, 100 mL) was added at below 10° C. The two layers were separated. Tothe aqueous layer was added 2N NaOH at below 10° C. to adjust the pH tobasic. The mixture was extracted with 200 mL of MTBE. The MTBE solutionwas concentrated to dryness to give 10 g of crude product. The crude waspurified using a 40 g silica gel column to give 7 g of product 2-2-2: ¹HNMR (400 MHz, CDCl₃) δ 7.45-7.32 (m, 5H), 6.04-5.95 (m, 1H), 5.84 (s,1H), 5.34-5.21 (m, 2H), 5.25 (s, 2H), 3.96 (d, J=8.3 Hz, 1H), 2.52-2.49(m, 4H), 1.85-1.74 (m, 4H); MS (ESI) m/z 285.1 (M+H).

Compound 2-2-2 (7.0 g, 24.6 mmol, 1.0 eq) was dissolved in THF. Thesolution was cooled with a water/ice/methanol batch. To the reactionmixture was added TMPMgCl—LiCl (1.0M, 34.4 mL, 1.4 eq) at 0° C. Afteraddition the reaction mixture was stirred for another 0.5 h and thencooled to −50° C. 3-Methoxy-2-uraldehyde (3.42 g, 27.1 mmol, 1.1 eq) wasadded at −50° C. The reaction mixture was gradually warmed up to −7° C.in 2.5 h and then quenched with 70 mL of saturated ammonium chlorideaqueous solution. The two layers were separated. The aqueous layer wasextracted with ethyl acetate twice (30 mL each). The combined organicswere washed sequentially with saturated aqueous ammonium chloride (30mL), water (30 mL) and brine (30 mL). After concentration, the crude wasloaded on a 230 g silica gel column, eluted with hexane and ethylacetate to give 5.8 g of product S2-3-2 as a mixture of the twodiastereomers: MS (ESI) m/z 411.2 (M+H).

Compound 2-3-2 (5.8 g, 14.15 mmol) was dissolved in 60 mL of dioxane. Tothe solution was added diisopropylethylamine (2.01 g, 15.56 mmol, 1.1eq) and BHT (50 mg). The mixture was stirred at 95° C. for 1 week. Themixture was concentrated and then dried under high vacuum to give 6.2 gof crude product S2-4-2 as a mixture of 4 diastereomers: MS (ESI) m/z411.2 (M+H).

The above crude compound S2-4-2 (14.15 mmol), DMSO (4.42 g, 56.6 mmol,4.0 eq) and triethylamine (5.72 g, 56.6 mmol, 4.0 eq) were mixed in 60mL of dichloromethane. After the mixture was cooled with an ice/watercooling bath, sulfur trioxide pyridine complex (4.73 g, 29.7 mmol, 2.1eq) was added. After addition, the cooling bath was removed. Afterstirring at rt for 5 h, additional 1 g of sulfur trioxide pyridine wasadded and the reaction was stirred for another 1 day. The reaction wascooled with an ice/water bath and then quenched with 40 mL of water. Theorganic layer was separated, washed with brine and concentrated to give6.8 g of crude product S2-5-2 as a mixture of 2 diastereomers: MS (ESI)m/z 409.2 (M+H).

The above crude compound S2-5-2 (˜14 mmol) was dissolved in 70 mL ofdichloromethane. The solution was cooled with a dry ice/acetone/waterbath. A solution of BCl₃ (1M, 19.6 mL, 1.4 eq) was added at −17° C. to−14° C. After addition the reaction mixture was stirred at the sametemperature for 20 min and then quenched with 30 mL of 20% aqueous K₃PO₃solution. The two layers were separated. The aqueous layer was extractedwith 10 mL of dichloromethane. The combined organics were washed withbrine and concentrated to give 5.7 g of crude compound S2-6-2 as a brownsolid (mixture of 2 diastereomers): MS (ESI) m/z 395.2 (M+H).

The above crude compound S2-6-2 (˜14 mmol) was dissolved in 60 mL ofDCM. The solution was cooled with an ice/water bath. To the solution wasadded 2,6-lutidine (2.4 g, 22.4 mmol, 1.6 eq) followed by TBSOTf (4.9 g,18.5 mmol, 1.3 eq). The reaction mixture was stirred with the coolingbath for 1 h and then quenched with 50 mL of water. The organic layerwas separated, washed with brine and concentrated. The crude was loadedon a 50 g silica gel column, eluted with hexane and ethyl acetate (9:1,500 mL) to give 2.1 g of compound S2-7-2 as a yellow solid: ¹H NMR (400MHz, CDCl₃) δ7.46-7.40 (m, 2H), 7.34-7.24 (m, 3H), 6.91-6.84 (m, 1H),6.06-6.02 (m, 1H), 5.29 (s, 2H), 4.05 (d, J=11.0 Hz, 1H), 3.00-2.94 (m,2H), 2.82-2.72 (m, 3H), 2.60-2.54 (m, 2H), 0.77 (s, 9H), 0.20 (s, 3H),0.00 (s, 3H); MS (ESI) m/z 509.3 (M+H).

Compound S2-1 (10 g, 43.3 mmol, 1.0 eq) and triethylamine (7.85 mL, 56.3mmol, 1.3 eq) were mixed in 150 mL of dichloromethane. The solution wascooled to below −20° C. Neat MsCl (3.85 mL, 49.8 mmol, 1.15 eq) wasadded to the reaction mixture dropwise maintaining the temperature below−20° C. After addition the reaction mixture was stirred for 30 min. Thereaction mixture was further cooled to −28° C. Morpholine (22.7 mL,259.8 mmol, 6.0 eq) was added dropwise keeping the temperature below−25° C. The reaction mixture was gradually warmed up to 5° C. over aperiod of 5 h. Water (150 mL) was added to quench the reaction. Theorganic layer was separated and concentrated to dryness. The residue wasdissolved in 200 mL of toluene, washed with water (100 mL×2) and brine(100 mL), and again concentrated to dryness. The crude was loaded on an80 g silica gel column and eluted with hexane and ethyl acetate (2:1 to3:2). The fractions containing the product were combined and thenconcentrated to 200 mL. After the solution was cooled to 0° C., 1N HCl(60 mL) was added. The two layers were separated. To the aqueous layerwas added MTBE (300 mL) and 2N NaOH (40 mL) while cooling with anice/water bath. The organic layer was separated and concentrated todryness to give 8.9 g of product S2-2-3: ¹H NMR (400 MHz, CDCl₃) δ7.45-7.32 (m, 5H), 5.95-5.85 (m, 1H), 5.81 (s, 1H), 5.35-5.29 (m, 2H),5.23 (s, 2H), 3.98 (d, J=8.2 Hz, 1H), 3.69 (t, J=4.6 Hz, 4H), 2.55-2.41(m, 4H); MS (ESI) m/z 301.1 (M+H).

Compound S2-2-3 (8.9 g, 29.6 mmol, 1.0 eq) was dissolved in 150 mL ofTHF. The solution was cooled to −102° C. using a liquid nitrogen/ethanolbath. n-BuLi (2.5M in hexane, 15.4 mL, 38.48 mmol, 1.3 eq) was addedslowly maintaining the temperature below −98° C. The reaction mixturewas stirred at −102° C. to −80° C. for 1 h. Solid MgBr₂-Et₂O (9.94 g,35.52 mmol, 1.2 eq) was added via a solid additional funnel over aperiod of 10 min maintaining temperature below −70° C. The resultingslurry was stirred at −70° C. for 30 min. At the same temperature solid3-methoxy-2furaldehyde (4.48 g, 38.48 mmol, 1.3 eq) was added. Thereaction mixture was gradually warmed up to −20° C. over a period of 1.5h and then quenched with 80 mL of saturated NH₄Cl. The organic layer wasseparated and concentrated to dryness. The residue was dissolved in 200mL of ethyl acetate, washed with water and brine and again concentratedto dryness. The crude was purified by silica gel (300 g) column elutingwith hexane and ethyl acetate (4:1 to 3:1) to give 4.84 g of compoundS2-3-3 as a 1 to 1 mixture of the 2 diastereomers: MS (ESI) m/z 427.2(M+H).

Compound S2-3-3 (4.84 g, 11.4 mmol), diiospropylethylamine (4.5 mL, 25.8mmol) and BHT (10 mg) were mixed in 150 mL 2-propanol. The reactionmixture was refluxed for 1 week. The mixture was concentrated todryness. The residue was purified by silica gel column eluting withhexane and acetone (4:1 to 2:1) to give 0.93 g product S2-4-3 as amixture of 4 diastereomers: MS (ESI) m/z 427.2 (M+H).

Compound S2-4-3 (0.9 g, 2.11 mmol, 1.0 eq) was dissolved in 4 mL ofdichloromethane. To the solution was added triethylamine (1.2 mL, 8.44mmol, 4.0 eq). The solution was cooled with an ice/water bath. A mixtureof sulfur trioxide pyridine complex (705 mg, 4.43 mmol, 2.1 eq) in DMSO(2.33 mL) was added at temperature below 5° C. The water bath wasremoved and the reaction mixture was stirred at room temperatureovernight. The reaction was cooled with an ice/water cooling bath andquenched with 20 mL of water. The organic layer was separated andconcentrated to dryness. The residue was dissolved in 100 mL of ethylacetate, washed with water (25 mL×3) and brine (25 mL) and concentratedto dryness. The residue was dissolved in 20 mL of toluene and thenevaporated to dryness to give 0.86 g crude product s2-5-3 as a mixtureof 2 diastereomers: MS (ESI) m/z 425.2 (M+H).

Compound S2-5-3 (0.86 g, 2 mmol, 1.0 eq) was dissolved in 12 mL ofdichloromethane. The solution was cooled to −17° C. To the solution wasadded BCl₃ (1M, 3 mL, 3 mmol, 1.5 eq) was added at below −15° C. Afteraddition the reaction mixture was stirred at −16° C. to −13° C. for 30min. Aqueous 15% K₃PO₄ was added to quench the reaction. The reactionmixture was extracted with 100 mL of dichloromethane, washed with water(30 mL×3) and brine. After concentration to dryness, 0.83 g of crudeproduct S2-6-3 was obtained: MS (ESI) m/z 411.2 (M+H).

Compound S2-6-3 (0.83 g, 3 mmol, 1.0 eq) was dissolved in 10 mL ofdichloromethane. To this solution was added 2,6-lutidine (0.46 mL, 4mmol, 2.0 eq). After the solution was cooled with an ice/water bath,TBSOTf (0.69 mL, 3 mmol, 1.5 eq) was added. After addition the reactionmixture was stirred at 0° C. for 1.5 h. Water (10 mL) was added toquench the reaction. The mixture was extracted with 100 mL of toluene.The organics was washed with water (20 mL×3) and brine (20 mL), andconcentrated. The crude was purified by a silica gel (20 g) columneluting with toluene followed by dichloromethane and acetone (9:1) togive 0.66 g of product S2-7-3 as a yellow solid: ¹H NMR (400 MHz, CDCl₃)δ 7.46-7.42 (m, 2H), 7.36-7.28 (m, 3H), 6.92-6.86 (m, 1H), 6.06 (m, 1H),5.30 (d, J=2.8 Hz, 2H), 3.71 (d, J=11 Hz, 1H), 2.98-2.92 (m, 2H),2.86-2.74 (m, 3H), 2.56-2.50 (m, 2), 0.78 (s, 9H), 0.20 (s, 3H), 0.00(s, 3H); MS (ESI) m/z 525.2 (M+H).

The following compounds were prepared according to Scheme 3.

To a solution of aniline S3-1 (15.0 g, 42.69 mmol, 1 eq, preparedaccording to literature procedures including J. Med. Chem., 2012, 55,606-622) and NaOAc (10.5 g, 128.07 mmol, 3 eq) in HOAc (100 mL) wasadded a solution of Br₂ (2.20 mL, 42.69 mmol, 1 eq) in HOAc (10 mL)dropwise via syringe at 17-19° C. while cooled in a cold water bath.After stirring at 20° C. for 20 min, more Br₂ (66 μL) in HOAc (1 mL) wasadded. After stirring for 5 min, the reaction was poured into ice/water.The resulting mixture was extracted with EtOAc (600 mL). The organicphase was separated, washed with 10% aqueous Na₂S₂O₃ solution, water,saturated aqueous sodium bicarbonate and brine. The resulting organicphase was dried over sodium sulfate, filtered and concentrated underreduced pressure. Flash chromatography on silica gel using 5%→6%EtOAc/hexanes yielded the desired product S3-2 as thick pale yellow oil(15.59 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.35 (m, 7H), 7.28-7.25(m, 1H), 7.15-7.13 (m, 2H), 5.01 (s, 2H), 4.27 (br s, 2H), 2.32 (d,J=2.4 Hz, 3H); MS (ESI) m/z 429.94, 431.92 (M+H).

To a solution of aniline S3-2 (908 mg, 2.11 mmol, 1 eq) in anhydrous THF(8 mL) was added a solution of LHMDS in THF (4.43 mL, 1.0M, 4.43 mmol,2.1 eq) at below −70° C. over 7 min. The resulting reaction solution wasstirred at −78° C. for 15 min. A solution of Boc₂O (484 mg, 2.22 mmol,1.05 eq) in THF (1 mL) was added at below −71° C. The reaction wasstirred at −78° C. for 30 min, and then the dry ice was removed from thecold bath. The reaction was then warmed up to −50° C., and allyl bromide(0.201 mL, 2.32 mmol, 1.1 eq) was added. The reaction was warmed up tort in 20 min, then it was heated at 50° C. for 3 h. More allyl bromide(0.201 mL, 2.32 mmol, 1.1 eq) was added. The resulting reaction washeated at 50° C. for 2 h, and then cooled to rt. The reaction wasdiluted with EtOAc (40 mL), washed with saturated aqueous NH₄Cl (2×30mL) and brine (30 mL). The resulting organic phase was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Flashchromatography on silica gel using 2%→5% EtOAc/hexanes yielded thedesired product S3-3 (1.06 g, 88%, ˜3:1 rotamers): ¹H NMR (400 MHz,CDCl₃) δ 7.39-7.34 (m, 7H), 7.29-7.25 (m, 1H), 7.04-7.00 (m, 2H),6.00-5.90 (m, 1H), 5.09-5.04 (m, 1H), 5.03-5.00 (m, 2.25H), 4.92 (d,J=10.4 Hz, 0.75H), 4.50 (dd, J=6.1, 14.6 Hz, 0.75H), 4.24 (dd, J=6.1,15.3 Hz, 0.25H), 4.04-3.97 (m, 1H), 2.42 (d, J=2.4 Hz, 2.25H), 2.40 (d,J=2.4 Hz, 0.75H), 1.54 (s, 2.25H), 1.44 (s, 6.75H); MS (ESI) m/z 591.99,593.98 (M+Na).

To a solution of bromide S3-3 (1.06 g, 1.86 mmol, 1 eq) in anhydrous THF(30 mL) was added a solution of ^(n)BuLi in hexanes (1.16 mL, 1.6M, 1.86mmol, 1.0 eq) dropwise at below −100° C. After stirring for 3 min, asolution of DMF (0.215 mL, 2.79 mmol, 1.5 eq) in THF (1 mL) was added atbelow −100° C. The resulting reaction solution was then allowed to warmup to −78° C. and stirred at that temperature for 35 min. Then saturatedaqueous NH₄Cl was added. The resulting mixture was allowed to warm up tort and extracted with EtOAc (40 mL). The organic phase was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. Flash chromatography on silica gel using 3%→12%EtOAc/hexanes yielded the desired product S3-4 (0.91 g, 94%, ˜2:1rotamers): ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 7.38-7.33 (m, 7H),7.28-7.24 (m, 1H), 7.02-6.99 (m, 2H), 5.93-5.79 (m, 1H), 5.04-4.96 (m,3.35H), 4.89 (d, J=9.8 Hz, 0.65H), 4.64 (dd, J=5.5, 14.6 Hz, 0.65H),4.32 (dd, J=5.5, 14.6 Hz, 0.35H), 3.97 (dd, J=7.9, 14.6 Hz, 0.35H), 3.90(dd, J=8.5, 14.6 Hz, 0.65H), 2.40 (d, J=1.8 Hz, 2H), 2.37 (d, J=1.8 Hz,1H), 1.51 (s, 3H), 1.36 (s, 6H); MS (ESI) m/z 542.11 (M+Na).

To a mixture of compound S3-4 (4.52 g, 8.71 mmol, 1 eq) and sarcosine(1.16 g, 13.06 mmol, 1.5 eq) was added DMF (72 mL) under nitrogen. Theresulting reaction mixture was stirred at 80° C. for 1 h 30 min, andcooled to rt. The resulting reaction mixture was then partitionedbetween EtOAc (500 mL) and water (720 mL). The organic phase wasseparated, washed with water (2×500 mL), brine (250 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. Flashchromatography on silica gel using 10%→60% EtOAc/hexanes yielded thedesired product S3-5 as a white solid (4.68 g, 98%). ¹H NMR (400 MHz,CDCl₃) δ 7.38-7.28 (m, 7H), 7.25-7.22 (m, 1H), 7.06-7.04 (m, 2H),4.96-4.84 (m, 2H), 4.25 (br s, 1H), 3.60 (br s, 1H), 2.98 (br t, J=7.3Hz, 1H), 2.78-2.64 (m, 2H), 2.35 (d, J=1.8 Hz, 3 H), 2.26 (br s, 4H),2.17-2.02 (m, 2H), 1.32 (br s, 9H); MS (ESI) m/z 547.14 (M+H).

General Procedure A (Michael-Dieckmann annulation). n-BuLi (170 μL, 1.6Min hexanes, 0.272 mmol, 1.4 eq) was added dropwise to a solution ofdiisopropylamine (41 μL, 0.291 mmol, 1.5 eq) in THF (1 mL) at −50° C.The reaction mixture was warmed up to −20° C. and re-cooled to below−70° C. TMEDA (44 μL, 0.291 mmol, 1.5 eq) was added. The reactionsolution was stirred at −78° C. for 5 min. A solution of racemiccompound S3-5 (106 mg, 0.194 mmol, 1 eq) in THF (1 mL) was addeddropwise via a cannula at below −72° C. The resulting red orangesolution was stirred at −78° C. for 30 min, and cooled to −100° C. usinga EtOH/liquid N₂ bath. A solution of enone S1-9-2 (104 mg, 0.194 mmol, 1eq) in THF (1 mL) was added to the reaction mixture. The reactionmixture was allowed to gradually warm up and then LHMDS (194 μL, 1.0M inTHF, 0.194 mmol, 1 eq) was added at ˜−90° C. The reaction mixture wasgradually warmed up to −10° C. A saturated aqueous NH₄Cl (20 mL)solution was added to the reaction. The reaction mixture was extractedwith EtOAc (40 mL). The organic phase was washed with brine (20 mL),dried over Na₂SO₄, and concentrated under reduced pressure. Flashchromatography on silica gel using 1%→50% EtOAc/hexanes yielded thedesired product S3-6-1 as a yellow solid (179 mg, 94%, ˜1:1diastereomers plus rotamers for each diastereomer): MS (ESI) m/z 987.52(M+H).

General Procedure B (de-allylation). To a mixture of compound S3-6-1(234 mg, 0.237 mmol, 1 eq), 1,3-dimethylbarbituric acid (370 mg, 2.37mmol, 10 eq) and Pd(PPh₃)₄ (14 mg, 0.024 mmol, 0.1 eq) was added DCM (5mL) under nitrogen. The resulting reaction solution was stirred at rtovernight. The reaction mixture was quenched with aqueous saturatedsodium bicarbonate (bubbling). The resulting reaction mixture wasstirred at rt for 10 min, and extracted with dichloromethane (3×10 mL).The combined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel using 20%→100%EtOAc/hexanes to yield the desired product S3-6-2 (159 mg, 74%, ˜1:1diastereomers plus rotamers for each diastereomer) as a yellow solid: MS(ESI) m/z 907.51 (M+H).

Compound S3-6-3 was also isolated in 15% yield along with compoundS3-6-2 (41% yield) and starting material (18% recovered) by using thegeneral procedure B when only half of the amounts of the reagents wereused. S3-6-3: MS (ESI) m/z 947.49 (M+H).

General Procedure C (HF desilylation and hydrogenation). Aqueous HF(48-50%, 0.5 mL) was added to a solution of compound S3-6-1 (27 mg,0.028 mmol, 1 eq) in dioxane (0.5 mL) in a polypropylene reaction vesselat rt. The mixture was stirred vigorously at rt overnight and pouredslowly into saturated aqueous NaHCO₃ (15 mL) (vigorously bubbling). Theresulting mixture was extracted with EtOAc (30 mL). The organic phasewas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was used directly inthe next step without further purification (MS (ESI) m/z 773.35 (M+H)).

Pd—C (10 wt %, 10 mg) was added in one portion into a solution of theabove crude product in a mixture of CH₃OH (1 mL) and HCl/water (1N, 84μL, 0.084 mmol, 3 eq) at rt. The reaction vessel was sealed and purgedwith hydrogen by briefly evacuating the flask followed by flushing withhydrogen gas (1 atm). The reaction mixture was stirred under a hydrogenatmosphere (1 atm) at rt for 40 min, and filtered through a small Celitepad. The cake was washed with MeOH. The filtrate was concentrated. Theresidue was purified by preparative reverse phase HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-γ 100A column[10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl/water;Solvent B: CH₃CN; injection volume: 3.0 mL (0.05N HCl/water); gradient:0→35% B in A over 20 min; mass-directed fraction collection]. Fractionscontaining the desired product were collected and freeze-dried to yieldcompound S3-7-1 (6.63 mg) and compound S3-7-2 (3.33 mg). The twodiastereomers of compound S3-7-1 was separated by a second HPLCpurification (5→30% B in A over 20 min). The early eluting diastereomeris S3-7-1-A, and the later one is S3-7-1-B.

S3-7-1-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.4Hz, 1H), 3.86 (s, 1H), 3.77-3.71 (m, 1H), 3.44 (dd, J=5.5, 13.3 Hz, 1H),3.35-3.17 (m, 3H), 3.12-3.04 (m, 5H), 2.99-2.93 (m, 1H), 2.84 (d, J=12.4Hz, 1H), 2.78-2.71 (m, 1H), 2.57-2.47 (m, 1H), 2.25-2.17 (m, 2H),2.09-2.01 (m, 1H), 1.83-1.72 (m, 2H), 1.60-1.50 (m, 1H), 1.03 (t, J=7.3Hz, 3H); MS (ESI) m/z 557.28 (M+H).

S3-7-1-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.0Hz, 1H), 3.87 (s, 1H), 3.78-3.71 (m, 1H), 3.45 (dd, J=5.5, 13.3 Hz, 1H),3.36-3.19 (m, 3H), 3.12-3.04 (m, 5H), 3.00-2.93 (m, 1H), 2.86 (d, J=12.4Hz, 1H), 2.78-2.70 (m, 1H), 2.58-2.48 (m, 1H), 2.23-2.14 (m, 2H),2.07-1.99 (m, 1H), 1.82-1.72 (m, 2H), 1.58-1.48 (m, 1H), 1.02 (t, J=7.3Hz, 3H); MS (ESI) m/z 557.28 (M+H).

S3-7-2: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, mixture ofdiastereomers) δ 4.76 (d, J=6.0 Hz, 1H), 4.22 (s, 1H), 3.78-3.72 (m,1H), 3.53-3.17 (m, 5H), 3.14-2.93 (m, 8H), 2.78-2.70 (m, 1H), 2.58-2.48(m, 1H), 2.25-2.15 (m, 2H), 2.08-1.99 (m, 1H), 1.89-1.76 (m, 4H),1.66-1.56 (m, 1H), 1.02 (t, J=6.9 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H); MS(ESI) m/z 599.37 (M+H).

Compound S3-7-3 was prepared from compound S3-6-2 by using the generalprocedure C.

S3-7-3-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.4Hz, 1H), 3.87 (s, 1H), 3.78-3.71 (m, 1H), 3.44 (dd, J=5.5, 12.8 Hz, 1H),3.36-3.29 (m, 1H), 3.13-3.02 (m, 5H), 2.97-2.87 (m, 1H), 2.80-2.71 (m,1H), 2.65-2.62 (m, 1H), 2.56-2.48 (m, 1H), 2.26-2.19 (m, 2H), 2.08-2.03(m, 1H), 1.61-1.52 (m, 1H); MS (ESI) m/z 515.25 (M+H).

S3-7-3-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=6.4Hz, 1H), 3.87 (s, 1H), 3.78-3.71 (m, 1H), 3.45 (dd, J=5.5, 13.3 Hz, 1H),3.37-3.29 (m, 1H), 3.12-3.02 (m, 5H), 2.98-2.91 (m, 1H), 2.76-2.70 (m,1H), 2.65-2.62 (m, 1H), 2.56-2.50 (m, 1H), 2.24-2.17 (m, 2H), 2.07-2.00(m, 1H), 1.61-1.52 (m, 1H); MS (ESI) m/z 515.25 (M+H).

General Procedure D-1 (Reductive Alkylation). To a solution of compoundS3-6-3 (22 mg, 0.023 mmol, 1 eq) in DCM (1 mL) was added a solution ofHCHO in water (37 wt %, 5.2 μL, 0.070 mmol, 3 eq), HOAc (2.6 μL, 0.046mmol, 2 eq) and sodium triacetoxyborohydride (10 mg, 0.046 mmol, 2 eq)subsequently. The resulting reaction mixture was stirred at rtovernight. More HCHO in water (37 wt %, 5.2 μL, 0.070 mmol, 3 eq), HOAc(2.6 μL, 0.046 mmol, 2 eq) and sodium triacetoxyborohydride (10 mg,0.046 mmol, 2 eq) were added. The resulting mixture was further stirredat rt for 6 h, and quenched by the addition of saturated aqueous sodiumbicarbonate and potassium phosphate buffer solution (pH=7). Theresulting mixture was extracted with DCM (2×20 mL). The combined organicphase was dried over anhydrous sodium sulfate, filtered, andconcentrated to give the crude reductive alkylation product S3-6-4: MS(ESI) m/z 961.52 (M+H).

The crude reductive alkylation product S3-6-4 was subjected to thegeneral procedure C for HF desilylation and hydrogenation to yield thedesired compound S3-7-4-A (3.50 mg, 24% over 3 steps), S3-7-4-B (2.59mg, 18% over 3 steps) and S3-7-5 (2.12 mg, 14% over 3 steps, a mixtureof diastereomers).

S3-7-4-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.4Hz, 1H), 3.81 (s, 1H), 3.78-3.71 (m, 1H), 3.44 (dd, J=6.4, 12.8 Hz, 1H),3.35-3.31 (m, 1H), 3.11-3.04 (m, 5H), 2.99-2.91 (m, 1H), 2.91 (s, 3H),2.82-2.72 (m, 2H), 2.57-2.50 (m, 1H), 2.24-2.17 (m, 2H), 2.08-2.01 (m,1H), 1.59-1.49 (m, 1H); MS (ESI) m/z 529.29 (M+H).

S3-7-4-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.4Hz, 1H), 3.80 (s, 1H), 3.78-3.71 (m, 1H), 3.45 (dd, J=5.0, 12.8 Hz, 1H),3.35-3.30 (m, 1H), 3.12-3.03 (m, 5H), 3.01-2.94 (m, 1H), 2.91 (s, 3H),2.81 (d, J=12.4 Hz, 1H), 2.76-2.71 (m, 1H), 2.58-2.48 (m, 1H), 2.22-2.15(m, 2H), 2.07-1.99 (m, 1H), 1.59-1.50 (m, 1H); MS (ESI) m/z 529.29(M+H).

S3-7-5: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, mixture ofdiastereomers) δ 4.76 (d, J=6.4 Hz, 1H), 4.20 (s, 0.5H), 4.11 (s, 0.5H),3.78-3.72 (m, 1H), 3.48-3.43 (m, 1H), 3.36-3.29 (m, 2H), 3.13-2.91 (m,11H), 2.79-2.71 (m, 1H), 2.56-2.50 (m, 1H), 2.26-2.16 (m, 2H), 2.08-1.99(m, 1H), 1.89-1.76 (m, 2H), 1.66-1.56 (m, 1H), 1.05-0.99 (m, 3H); MS(ESI) m/z 571.33 (M+H).

Compound S3-7-6 was prepared from compound S3-6-2 by using the generalprocedure D-1 (with acetaldehyde) and C.

S3-7-6-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.4Hz, 1H), 3.86 (s, 1H), 3.78-3.71 (m, 1H), 3.47-3.40 (m, 2H), 3.36-3.29(m, 2H), 3.12-3.04 (m, 5H), 2.98-2.90 (m, 1H), 2.83 (d, J=12.8 Hz, 1H),2.78-2.71 (m, 1H), 2.55-2.49 (m, 1H), 2.24-2.17 (m, 2H), 2.07-2.00 (m,1H), 1.58-1.49 (m, 1H), 1.36 (t, J=6.9 Hz, 3H); MS (ESI) m/z 543.26(M+H).

S3-7-6-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.0Hz, 1H), 3.86 (s, 1H), 3.78-3.71 (m, 1H), 3.48-3.41 (m, 2H), 3.36-3.29(m, 2H), 3.13-3.04 (m, 5H), 3.00-2.92 (m, 1H), 2.84 (d, J=12.4 Hz, 1H),2.76-2.70 (m, 1H), 2.58-2.48 (m, 1H), 2.22-2.15 (m, 2H), 2.07-0.99 (m,1H), 1.59-1.49 (m, 1H), 1.36 (t, J=7.3 Hz, 3H); MS (ESI) m/z 543.26(M+H).

Compound S3-7-7 was prepared from compound S3-6-2 by using the generalprocedure D-1 (with acetone) and C. The two diastereomers were separatedby HPLC.

S3-7-7-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.4Hz, 1H), 3.95 (s, 1H), 3.86-3.71 (m, 2H), 3.45 (dd, J=5.5, 12.8 Hz, 1H),3.38-3.29 (m, 1H), 3.13-3.02 (m, 5H), 2.96-2.92 (m, 1H), 2.82 (d, J=12.8Hz, 1H), 2.78-2.71 (m, 1H), 2.58-2.49 (m, 1H), 2.25-2.18 (m, 2H),2.09-2.00 (m, 1H), 1.61-1.51 (m, 1H), 1.42 (d, J=6.9 Hz, 3H), 1.38 (d,J=6.4 Hz, 3H); MS (ESI) m/z 557.27 (M+H).

S3-7-7-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.0Hz, 1H), 3.95 (s, 1H), 3.86-3.71 (m, 2H), 3.45 (dd, J=5.5, 12.8 Hz, 1H),3.35-3.29 (m, 1H), 3.12-2.92 (m, 6H), 2.83 (d, J=12.4 Hz, 1H), 2.78-2.71(m, 1H), 2.57-2.48 (m, 1H), 2.26-2.15 (m, 2H), 2.07-1.99 (m, 1H),1.60-1.51 (m, 1H), 1.43 (d, J=6.9 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H); MS(ESI) m/z 557.27 (M+H).

General Procedure D-2 (cyclopropylation). To a solution of compoundS3-6-2 (20 mg, 0.022 mmol, 1 eq) in MeOH (1 mL) was added 4 Å molecularsieves, HOAc (7.6 μL, 0.132 mmol, 6 eq),[(1-ethoxycyclopropyl)oxy]trimethylsilane (26.4 μL, 0.132 mmol, 6 eq),and sodium cyanoborohydride (5.6 mg, 0.088 mmol, 4 eq) subsequently. Theresulting reaction mixture was stirred at 55° C. overnight. Theresulting mixture was cooled to rt, and filtered through a pad ofCelite. The cake was washed with DCM. The filtrate was washed with amixture of saturated aqueous sodium bicarbonate and potassium phosphatebuffer solution (pH=7). The resulting organic phase was dried overanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate,20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1%HCO₂H; injection volume: 3.0 mL (CH₃CN); gradient: 20→100% B in A over13 min; mass-directed fraction collection]. Fractions containing thedesired product were collected and freeze-dried to yield the desiredproduct (7.8 mg, 37%). MS (ESI) m/z 947.53 (M+H).

The above product was subjected to the general procedure C for HFdesilylation and hydrogenation to yield the desired compound S3-7-8.

S3-7-8-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=6.9Hz, 1H), 3.98 (s, 1H), 3.77-3.71 (m, 1H), 3.44 (dd, J=5.0, 10.3 Hz, 1H),3.38-3.29 (m, 1H), 3.12-2.95 (m, 8H), 2.78-2.72 (m, 1H), 2.58-2.49 (m,1H), 2.25-2.18 (m, 2H), 2.09-2.01 (m, 1H), 1.61-1.51 (m, 1H), 1.10-0.95(m, 4H); MS (ESI) m/z 555.26 (M+H).

S3-7-8-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=6.4Hz, 1H), 3.98 (s, 1H), 3.77-3.70 (m, 1H), 3.44 (dd, J=6.6, 13.3 Hz, 1H),3.35-3.24 (m, 1H), 3.11-2.95 (m, 8H), 2.76-2.69 (m, 1H), 2.57-2.48 (m,1H), 2.25-2.15 (m, 2H), 2.06-1.98 (m, 1H), 1.60-1.50 (m, 1H), 1.08-0.93(m, 4H); MS (ESI) m/z 555.26 (M+H).

Compound S3-7-9 was prepared from compound S3-6-2 by using the generalprocedure D-1 twice (with acetaldehyde followed by formaldehyde) andgeneral procedure C.

S3-7-9-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.0Hz, 1H), 4.21 (s, 0.5H), 4.12 (s, 0.5H), 3.78-3.71 (m, 1H), 3.53-3.42(m, 2H), 3.36-3.30 (m, 2H), 3.12-2.90 (m, 10H), 2.78-2.70 (m, 1H),2.57-2.49 (m, 1H), 2.25-2.17 (m, 2H), 2.09-2.01 (m, 1H), 1.68-1.54 (m,1H), 1.43-1.34 (m, 3H); MS (ESI) m/z 557.31 (M+H).

S3-7-9-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers) δ4.76 (d, J=6.0 Hz, 1H), 4.21 (s, 0.5H), 4.12 (s, 0.5H), 3.78-3.72 (m,1H), 3.52-3.43 (m, 2H), 3.36-3.30 (m, 2H), 3.13-2.94 (m, 10H), 2.78-2.70(m, 1H), 2.58-2.49 (m, 1H), 2.25-2.16 (m, 2H), 2.08-1.99 (m, 1H),1.68-1.56 (m, 1H), 1.43-1.36 (m, 3H); MS (ESI) m/z 557.31 (M+H).

Compound S3-7-10 was prepared from compound S3-6-2 by using the generalprocedure D (with excess acetaldehyde) and C.

S3-7-10-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.0Hz, 1H), 4.23 (s, 1H), 3.78-3.71 (m, 1H), 3.61-3.54 (m, 1H), 3.48-3.42(m, 3H), 3.34-3.30 (m, 1H), 3.14-2.96 (m, 7H), 2.92 (d, J=12.8 Hz, 1H),2.78-2.72 (m, 1H), 2.57-2.48 (m, 1H), 2.25-2.18 (m, 2H), 2.08-1.99 (m,2H), 1.66-1.56 (m, 1H), 1.40 (t, J=6.9 Hz, 6H); MS (ESI) m/z 571.31(M+H).

S3-7-10-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.0Hz, 1H), 4.24 (s, 1H), 3.78-3.72 (m, 1H), 3.62-3.57 (m, 1H), 3.50-3.43(m, 3H), 3.34-3.30 (m, 1H), 3.12-2.98 (m, 7H), 2.92 (d, J=12.8 Hz, 1H),2.78-2.72 (m, 1H), 2.58-2.49 (m, 1H), 2.22-2.16 (m, 2H), 2.06-1.99 (m,2H), 1.66-1.56 (m, 1H), 1.41 (t, J=7.3 Hz, 6H); MS (ESI) m/z 571.31(M+H).

To a solution of compound S3-6-2 (21 mg, 0.023 mmol, 1 eq) and^(i)Pr₂NEt (11.9 μL, 0.069 mmol, 3 eq) in DCM (1 mL) was added acetylchloride (2.5 μL, 0.035 mmol, 1.5 eq) at 0° C. The resulting reactionmixture was stirred at 0° C. for 25 min. Potassium phosphate buffersolution (pH=7) was added. The resulting mixture was extracted with DCM(3×10 mL). The combined organic phase was dried over anhydrous sodiumsulfate, filtered, and concentrated. LC-MS showed a mixture of thedesired product and diacylation by-product. The residue was dissolved inMeOH (0.5 mL). Potassium carbonate (6.4 mg, 0.46 mmol, 2 eq) was added.The resulting reaction mixture was stirred at rt for 45 min and quenchedwith saturated aqueous NH₄Cl and potassium phosphate buffer solution(pH=7). The resulting mixture was extracted with DCM (3×10 mL). Thecombined organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated.

The above crude product, MS (ESI) m/z 949.56 (M+H), was subjected to thegeneral procedure C for HF desilylation and hydrogenation to yield thedesired compound S3-7-11 (3.95 mg, 27% over 3 steps): ¹H NMR (400 MHz,CD₃OD, hydrochloride salt, mixture of diastereomers) δ 4.75 (d, J=5.5Hz, 1H), 4.70-4.65 (m, 1H), 3.77-3.70 (m, 1H), 3.46-3.41 (m, 1H),3.35-3.29 (m, 2H), 3.12-3.00 (m, 5H), 2.96-2.89 (m, 1H), 2.78-2.72 (m,1H), 2.54-2.46 (m, 1H), 2.41-2.33 (m, 2H), 2.07-2.04 (m, 4H), 1.60-1.54(m, 1H); MS (ESI) m/z 557.26 (M+H).

To a solution of compound S3-6-2 (21 mg, 0.023 mmol, 1 eq) and^(i)Pr₂NEt (11.9 μL, 0.069 mmol, 3 eq) in DCM (1 mL) was added methanesulfonic anhydride (6 mg, 0.035 mmol, 1.5 eq) at 0° C. The resultingreaction mixture was stirred at 0° C. for 1 h and 35 min and then rtovernight. More ^(i)Pr₂NEt (11.9 μL, 0.069 mmol, 3 eq) and methanesulfonic anhydride (6 mg, 0.035 mmol, 1.5 eq) were added at 0° C. Theresulting reaction mixture was stirred at that temperature for 1 h.Saturated aqueous NH₄Cl and potassium phosphate buffer solution (pH=7)were added. The resulting mixture was extracted with DCM (3×10 mL). Thecombined organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated to yield the crude product: MS (ESI) m/z985.52 (M+H). This crude product was subjected to the general procedureC for HF desilyllation and hydrogenation to yield the desired compoundS3-7-12 (3.39 mg, 22% over 3 steps): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt, mixture of diastereomers) δ 4.77-4.75 (m, 1H), 4.08(d, J=4.6 Hz, 1H), 3.76-3.70 (m, 1H), 3.44 (d, J=5.5, 13.3 Hz, 1H),3.33-3.29 (m, 1H), 3.18-3.01 (m, 8H), 2.96-2.92 (m, 1H), 2.78-2.72 (m,1H), 2.53-2.38 (m, 3H), 2.29-2.23 (m, 1H), 2.08-2.00 (m, 1H), 1.70-1.62(m, 1H); MS (ESI) m/z 593.17 (M+H).

To a solution of compound S3-6-2 (30 mg, 0.033 mmol, 1 eq) and^(i)Pr₂NEt (40 μL, 0.23 mmol, 7 eq) in DCM (1.5 mL) was addeddimethylaminoacetyl chloride hydrochloride (26 mg, 0.165 mmol, 5 eq) atrt. The resulting reaction mixture was stirred at rt overnight.Potassium phosphate buffer solution (pH=7) was added. The resultingmixture was extracted with DCM (3×10 mL). The combined organic phase wasdried over anhydrous sodium sulfate, filtered, and concentrated to yieldthe crude product: MS (ESI) m/z 992.59 (M+H).

General Procedure E (global deprotection). To a solution of the abovecrude product in DCM (0.2 mL) was added dimethyl sulfide (7.3 μL, 0.099mmol, 3 eq) at 0° C., followed by methane sulfonic acid (0.1 mL). Theresulting reaction solution was stirred at rt for 2 h, and DCM wasevaporated by blowing nitrogen to the reaction with stirring. Then DCM(50 μL) and dimethyl sulfide (10 μL) were added, and the resultingreaction solution was stirred at rt for 3 days. Again solvent wasevaporated and the residue was diluted with 0.05N HCl in water solution.The resulting solution was purified by preparative reverse phase HPLC ona Waters Autopurification system using a Phenomenex Polymerx 10μ RP-γ100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05NHCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05N HCl/water);gradient: 0→30% B in A over 20 min; mass-directed fraction collection].Fractions containing the desired product were collected and freeze-driedto yield compound S3-7-13-A (3.25 mg, 15% over 2 steps) as the earlyeluting diastereomer and compound S3-7-13-B (8.02 mg, 36% over 2 steps)as the later eluting diastereomer.

S3-7-13-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, rotamers) δ 4.75(d, J=6.4 Hz, 1H), 4.71-4.70 (m, 1H), 4.08, 4.03 (ABq, J=15.6 Hz, 2H),3.78-3.72 (m, 1H), 3.44 (dd, J=5.4, 12.9 Hz, 1H), 3.36-3.29 (m, 1H),3.09-3.04 (m, 5H), 2.99-2.90 (m, 7H), 2.79-2.72 (m, 1H), 2.57-2.47 (m,2H), 2.39-2.32 (m, 2H), 2.08-2.00 (m, 1H), 1.64-1.56 (m, 1H); MS (ESI)m/z 600.31 (M+H).

S3-7-13-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, rotamers) δ4.77-4.76 (m, 1H), 4.72-4.71 (m, 1H), 4.14-4.03 (m, 2H), 3.78-3.72 (m,1H), 3.44 (dd, J=5.0, 12.8 Hz, 1H), 3.36-3.29 (m, 1H), 3.14-2.91 (m,12H), 2.79-2.72 (m, 1H), 2.56-2.48 (m, 2H), 2.36-2.34 (m, 2H), 2.07-1.98(m, 1H), 1.64-1.56 (m, 1H); MS (ESI) m/z 600.31 (M+H).

The following compounds were prepared according to Scheme 4.

To an ice-cooled solution of 2-methoxy-6-methylaniline (S4-1, 25.12 g,183.10 mmol, 1 eq) in CH₃OH (79 mL) and HOAc (25 mL) was added asolution of bromine (9.41 mL, 183.10 mmol, 1 eq) in HOAc (79 mL) dropwise via an addition funnel. The reaction mixture was allowed to warm tort and stirred for 2 h after complete addition. EtOAc (150 mL) wasadded, and the solid was collected by filtration and washed with moreEtOAc, yielding 37.20 g of compound S4-2 as an off-white solid (HBrsalt).

4-Bromo-2-methoxy-6-methylaniline (S4-2, HBr salt, 20.00 g, 92.70 mmol,1 eq) was suspended in concentrated aqueous HCl (22 mL) and crushed ice(76 g) cooled in an ice-bath. A solution of NaNO₂ (6.52 g, 94.60 mmol,1.02 eq) in H₂O (22 mL) was added drop wise. The resulting mixture wasstirred at 0° C. for 30 min and neutralized with aqueous Na₂CO₃. Asuspension of CuCN (10.40 g, 115.90 mmol, 1.25 eq) in H₂O (44 mL) wasmixed with a solution of NaCN (14.40 g, 294.80 mmol, 3.18 eq) in 22 mLof H₂O and cooled in an ice-bath. The initial diazonium salt mixture wasthen added to the CuCN and NaCN mixture with vigorous stirring whilemaintaining the temperature at 0° C. (toluene (180 mL) was also added inportions during the addition). The reaction mixture was stirred at 0° C.for 1 h, at rt for 2 h, and at 50° C. for another 1 h. After cooling tort, the layers were separated. The aqueous layer was extracted withtoluene. The combined organic layers were washed with brine, dried overmagnesium sulfate, and concentrated. The residue was passed through asilica gel plug, washed with toluene, and concentrated to yield 14.50 gof compound S4-3 as a light yellow solid.

To a solution of S4-3 (11.34 g, 50.20 mmol, 1 eq) in THF (100 mL) wasadded 1.5M DIBAL-H in toluene (40.10 mL, 60.20 mmol, 1.2 eq) slowly at−78° C. The reaction was allowed to warm to rt gradually and stirredovernight. After re-cooled to 0° C., the reaction was carefully quenchedby 1N aqueous HCl. The resulting mixture was stirred at rt for 1 h andextracted three times with EtOAc. The combined EtOAc layers were washedwith H₂O, saturated aqueous NaHCO₃ and brine, dried over magnesiumsulfate, and concentrated to provide compound S4-4 as a yellow solid,which was used directly in the next step.

To a suspension of S4-4 (50.20 mmol, 1 eq) in t-BuOH (200 mL) was addeda solution of NaClO₂ (11.34 g, 100.30 mmol, 2 eq) and NaH₂PO₄ (34.6 g,250.80 mmol, 5 eq) in H₂O (100 mL) via an addition funnel. Aftercomplete addition, 2-methyl-2-butene (42.40 mL, 0.40 mol, 8 eq) wasadded. The resulting homogenous solution was stirred at rt for 30 min,and volatiles were removed. The residue was suspended in 150 mL of H₂O.The solution was acidified to pH=1 with 1N aqueous HCl and extractedthree times with t-butyl methyl ether. The combined organic solution wasextracted three times with 1N aqueous NaOH. The combined aqueoussolution was acidified with 6N aqueous HCl, and extracted three timeswith EtOAc. The combined EtOAc extracts were washed with brine, driedover magnesium sulfate, and concentrated to provide 8.64 g of thebenzoic acid intermediate (4-4-a) as an off-white solid, which was useddirectly in the next step.

To a solution of the above benzoic acid (8.64 g, 35.20 mmol, 1 eq) indichloromethane (70 mL) was added oxalyl chloride (3.76 mL, 42.30 mmol,1.2 eq), followed by a couple of drops of DMF (caution: gas evolution).The mixture was stirred at rt for 30 min and the volatiles wereevaporated under reduce pressure. The residue was further dried underhigh vacuum to afford the crude benzoyl chloride. The crude benzoylchloride was re-dissolved in dichloromethane (70 mL). Triethylamine(12.3 mL, 88.10 mmol, 2.5 eq), phenol (3.98 g, 42.30 mmol, 1.2 eq) andDMAP (0.43 g, 3.52 mmol, 0.1 eq) were added. The mixture was stirred atrt for 1 h. The solvent was evaporated. The residue was suspended inEtOAc, and the precipitate was filtered off. The organic solution wasthen washed with 1N aqueous HCl (three times), H₂O, saturated aqueousNaHCO₃, and brine, dried over sodium sulfate, filtered and concentrated.Purification of the residue by flash chromatography gave compound S4-5(10.05 g, 89%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ7.41-7.45 (m, 2 H), 7.22-7.27 (m, 3H), 7.04 (d, J=0.9 Hz, 1H), 6.97 (d,J=0.9 Hz, 1H), 3.87 (s, 3H), 2.42 (s, 3H); MS (ESI) m/z 319.0 (M−H).

Compound S4-5 (20 g, 62.5 mmol, 1.0 eq),2,4,6-trivinylcyclotriboroxane-pyridine complex (7.8 g, 31.25 mmol, 0.50eq), Pd(PPh₃)₄ (2.2 g, 1.88 mmol, 0.030 eq) and K₂CO₃ (17.25 g, 125mmol, 2.0 eq) were added to a vessel in 1.4 mL dioxane:H₂O (3:1, V:V).The mixture was bubbled with N₂ to remove O₂ for 6 times. The mixturewas heated to reflux for 19 h. The mixture was concentrated. The residuepartitioned between EtOAc and water. The organic layer was dried overNa₂SO₄ and evaporated to dryness. The crude compound was purified bycolumn chromatography on silica gel, eluting with (petroleumether:EtOAc=200:1 to 100:1 to 50:1 gradient). This yielded 14.8 g(88.3%) compound S4-5-a as a light yellow solid: ¹H NMR (400 MHz, CDCl₃)δ 7.38-7.34 (m, 2H), 7.27-7.16 (m, 3H), 6.83-6.76 (m, 2H), 6.65-6.60 (m,1H), 5.72 (d, J=17.6 Hz, 1H), 5.25 (d, J=11.2 Hz, 1H), 3.83 (s, 3H),2.38 (s, 3H); MS (ESI) m/z 269.1 (M+H).

An ozone-enriched steam of oxygen was bubbled through a cold (−78° C.)solution of compound S4-5-a (21 g, 78.3 mmol, 1.0 eq) in anhydrousCH₂Cl₂ until it turned light blue. The reaction was followed by TLC. Thesolution was purged with argon at −78° C. for 10 min to remove theexcess O₃. CH₃SCH₃ (50 mL) was added into the reaction mixture and wasstirred for 5 hours from −78° C. to 25° C. The reaction wasconcentrated. The crude compound was purified by column chromatographyon silica gel, eluting with (petroleum ether:EtOAc=100:1 to 50:1 to 30:1gradient) to yield 13 g (61.6%) compound S4-6 as a light yellow solid:¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.46-7.41 (m, 2H), 7.36-7.22 (m,5H), 3.92 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z 271.1 (M+H).

Compound S4-6 (1.8 g, 6.62 mmol, 1 eq) was dissolved in HOAc. Bromine(1.6 mL, 26.5 mmol, 4 eq) was added dropwise into the solution. Thereaction mixture was stirred for 1 hour at rt. The mixture wasconcentrated. The residue was dissolved in EtOAc and washed withsaturated NaHCO₃, brine and water. The organics were dried over Na₂SO₄and concentrated to dryness to afford 1.9 g bromo compound S4-6-a as alight yellow solid.

BBr₃ (4.9 g, 1.9 mL, 19.5 mmol, 1.5 eq) was added to a CH₂Cl₂ solution(30 mL) of S4-6-a (3.5 g, 13.0 mmol, 1.0 eq) at −78° C. The reaction wasstirred from −78° C. to 25° C. for 1.5 h, was quenched with saturatedNaHCO₃ and was extracted with EtOAc. The combined EtOAc extracts weredried (Na₂SO₄) and concentrated to yield 3.3 g of crude phenol S4-6-b.

K₂CO₃ (3.6 g, 26.0 mmol, 2.0 eq) and benzylbromide (4.2 g, 26.0 mmol,2.0 eq) were added to a solution of compound S4-6-b (3.3 g, 13.0 mmol,1.0 eq) in DMF (15 mL). The reaction mixture was stirred at rt for 2 h.The reaction mixture was filtered (EtOAc wash). Water (150 mL) wasadded, and the mixture was extracted with EtOAc. The organic layer wasdried over Na₂SO₄ and concentrated. The crude compound was purified bycolumn chromatography on silica gel, eluting with (petroleumether:EtOAc=100:1 to 50:1 gradient). This gave 3.5 g (61.7% for 3 steps)of compound S4-7 as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ10.43 (s, 1H), 7.46-7.30 (m, 9H), 7.08-7.05 (m, 2H), 5.17 (s, 2H), 2.52(s, 3H); MS (ESI) m/z 425.1 (M+H).

To a solution of compound S4-7 (5 g, 11.8 mmol, 1.0 eq) in anhydrous DMFwas added CH₃O₂CCF₂SO₂F (11.3 g, 59 mmol, 5.0 eq) and CuI (4.5 g, 23.6mmol, 2.0 eq). The reaction was heated to 100° C. for 20 h. The mixturewas filtered and washed with EtOAc. The solution was concentrated andextracted with EtOAc and water. The organic layer was dried over Na₂SO₄and concentrated to give 7 g of the crude compound S4-8 as brown oil: ¹HNMR (400 MHz, CDCl₃) δ 10.35-10.32 (m, 1 H), 7.40-7.28 (m, 9H),7.02-6.83 (m, 2H), 5.17 (s, 2H), 2.55-2.51 (m, 3H); MS (ESI) m/z 415.1(M+H).

To a solution of S4-8 (4.02 g, 9.70 mmol) in THF (39 mL) was added asolution of Ti(OEt)₄ (technical grade, ˜20% Ti; 20.1 mL, 19.4 mmol, 2.0eq) under N₂ atmosphere, followed by (S)-tert-butanesulfinamide (1.76 g,14.6 mmol, 1.5 eq). The resulting yellow solution was stirred at rt andconversion was followed by LC-MS. Upon completion, the reaction mixturewas poured into 80 mL brine while rapidly stirring, and stirring wascontinued for another 30 min. The resulting suspension was filteredthrough a plug of Celite, and the filter cake was washed with EtOAc. Thefiltrate was transferred to a separation funnel where the organic layerwas washed with brine, dried over sodium sulfate, and concentrated underreduced pressure. Purification of the residue by Biotage flashchromatography gave compound S4-9 as an off-white foam (4.07 g, 81%): ¹HNMR (400 MHz, CDCl₃) δ 8.96 (br. s, 1H), 7.23-7.45 (m, 9H), 7.08 (d,J=7.3 Hz, 2H), 5.25 (s, 2H), 2.58 (q, J=3.2 Hz, 3H), 1.24 (s, 9H); MS(ESI) m/z 518.5 (M+H).

A flame dried flask was charged with magnesium turnings (10.94 g, 450mmol) and catalytic amounts of I₂ (761.4 mg, 3 mmol), which was heatedwith heat gun under N₂ for 2 min. Once they were cooled to rt, THF (150mL) was added. A small portion solution of 2-(2-bromoethyl)-1,3-dioxane(20.3 mL, 150 mmol) in THF (50 mL) was added. After the reactioncommenced, the rest of 2-(2-bromoethyl)-1,3-dioxane solution was addedvia cannula. The reaction mixture was periodically cooled in a rt waterbath to prevent refluxing. After addition of the2-(2-bromoethyl)-1,3-dioxane solution was completed, the reactionmixture was stirred for 2 h. The solution was then transferred to asure-sealed bottle to remove the remaining Mg and stored in fridge forfuture use.

To a solution of compound S4-9 (2.32 g, 4.49 mmol) in THF (18 mL) wasadded the Grignard solution (11.2 mL) prepared above at −78° C. in 10min. After the mixture was stirred at this temperature for 1 h 30 min,the cold bath was removed. When the inner temperature reached −48° C.,sat. aq. NH₄Cl (30 mL) was added. The layers were separated. The aqueouslayer was extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over sodium sulfate, and concentrated underreduced pressure to yield the crude product as a white solid, which wassuspended in 25 mL heptane. The mixture was stirred at rt for 1 h 30min, the solid was collected by filtration and washed with small portionof heptane. Further dried under high vacuum provided compound S4-10 as awhite solid (2.70 g, 95%, single diastereomer): ¹H NMR (400 MHz, CDCl₃)δ 7.41 (d, J=7.3 Hz, 2H), 7.31-7.37 (m, 5H), 7.22 (t, J=7.3 Hz, 1H),7.15 (s, 1H), 7.05 (d, J=7.3 Hz, 2H), 5.20 (s, 2H), 4.88 (dd, J=7.8,11.2 Hz, 1H), 4.47 (t, J=4.6 Hz, 1H), 4.04-4.09 (m, 2H), 3.71-3.75 (m,3H), 2.52 (q, J=3.2 Hz, 3H), 1.98-2.09 (m, 1H), 1.81-1.90 (m, 2H),1.62-1.71 (m, 1H), 1.47-1.57 (m, 1H), 1.30 (d, J=11.9 Hz, 1H), 1.17 (s,9H); MS (ESI) m/z 634.6 (M+H).

Compound S4-10 (2.70 g, 4.26 mmol) was added to the mixture of TFA-H₂O(21 mL-21 mL) cooled in an ice bath. The resulting mixture was thenstirred at 6° C. and conversion was followed by LC-MS. Upon completion,the reaction mixture was cooled to −20° C., and NaBH(OAc)₃ was added.Temperature was then allowed to warm to rt. After the mixture wasstirred at rt for 1 h, it was re-cooled to 0° C. The pH of the solutionwas adjusted to ˜8 with 45% aq. KOH. The aqueous solution was extractedwith MTBE (×3). The combined organic layers were washed with brine,dried over sodium sulfate, and concentrated under reduced pressure.Purification of the residue by Biotage flash chromatography gavecompound S4-11 as a light yellow oil (1.29 g, 66%, single enantiomer A):¹H NMR (400 MHz, CDCl₃) δ 7.67 (s, 1H), 7.22-7.46 (m, 8H), 7.08 (d,J=7.3 Hz, 2H), 5.22 (ABq, J=11.4, 18.4 Hz, 2H), 4.64-4.69 (m, 1H),3.02-3.16 (m, 2H), 2.53 (q, J=3.2 Hz, 3H), 2.21-2.30 (m, 1H), 1.85 (brs, 1H), 1.73-1.80 (m, 2H), 1.44-1.52 (m, 1H); MS (ESI) m/z 456.5 (M+H).

To a solution of compound S4-11 (164 mg, 0.36 mmol, 1 eq) in MeCN (1.5mL) was added HOAc (82 μL, 1.44 mmol, 4.0 eq) followed by benzaldehyde(109 μL, 1.08 mmol, 3.0 eq) and STAB (229 mg, 1.08 mmol, 3.0 eq). Theresulting reaction mixture was stirred at rt overnight, diluted withEtOAc. Saturated aqueous sodium bicarbonate was added. The organic phasewas separated and washed with brine. The resulting organic phase wasdried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. Flash chromatography on silica gel using 0%→10%EtOAc/hexanes yielded the desired product S4-12 (194 mg, 99%, singleenantiomer A) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H),7.47-7.45 (m, 2H), 7.40-7.35 (m, 5H), 7.30-7.24 (m, 6H), 7.11-7.09 (m,2H), 5.25, 5.21 (ABq, J=11.6 Hz, 2H), 3.95 (t, J=7.9 Hz, 1H), 3.78 (d,J=13.4 Hz, 1H), 3.19-3.13 (m, 2H), 2.57 (q, J=1.8 Hz, 3H), 2.35-2.26 (m,2H), 1.84-1.78 (m, 2H), 1.64-1.55 (m, 1H); MS (ESI) m/z 546.30 (M+H).

Compound S4-13-1 was prepared in 98% yield from S4-12 (single enantiomerA) and N-diallyl enone S1-9-2 using general procedure A. S4-13-1 (singlediastereomer A, light yellow solid): ¹H NMR (400 MHz, CDCl₃) δ 15.76 (s,1H), 7.85 (s, 1H), 7.53-7.48 (m, 4H), 7.42-7.34 (m, 5H), 7.31-7.19 (m,6H), 5.88-5.78 (m, 2H), 5.39 (s, 2H), 5.28 (s, 2H), 5.24 (d, J=17.7 Hz,2H), 5.15 (d, J=9.8 Hz, 2 H), 4.13 (d, J=10.4 Hz, 1H), 3.84 (t, J=8.4Hz, 1H), 3.65 (d, J=13.4 Hz, 1H), 3.36 (br d, J=11.0 Hz, 2H), 3.28-3.10(m, 5H), 3.00 (t, J=15.3 Hz, 1H), 2.87-2.81 (m, 1H), 2.55-2.45 (m, 2H),2.35-2.29 (m, 2H), 2.15 (d, J=14.0 Hz, 1H), 1.81-1.50 (m, 3H), 0.86 (s,9H), 0.29 (s, 3H), 0.17 (s, 3H); MS (ESI) m/z 986.55 (M+H).

Compound S4-13-4 was prepared in 79% yield from racemic S4-12 andN-methylethyl enone S1-9-1 using general procedure A. S4-13-4 (˜1:1mixture of two diastereomers, light yellow foam): 1H NMR (400 MHz,CDCl₃) δ 15.78 (br s, 1H), 7.94 (s, 0.5H), 7.84 (s, 0.5H), 7.52-7.44 (m,4H), 7.41-7.19 (m, 11H), 5.37 (s, 2H), 5.29-5.27 (m, 2H), 4.06-4.03 (m,0.5H), 3.85-3.78 (m, 1H), 3.64 (d, J=12.8 Hz, 0.5H), 3.31-3.15 (m, 4H),2.92-2.65 (m, 4H), 2.58-2.44 (m, 2H), 2.379 (s, 1.5H), 2.376 (s, 1.5H),2.34-2.27 (m, 2H), 2.18 (d, J=14.6 Hz, 1H), 1.79-1.72 (m, 2H), 1.55-1.48(m, 1H), 1.13 (t, J=7.3 Hz, 3H), 0.86 (s, 4.5H), 0.85 (s, 4.5H), 0.29(s, 3H), 0.18 (s, 1.5H), 0.17 (s, 1.5H); MS (ESI) m/z 948.56 (M+H).

Compound S4-13-5 was prepared in 64% yield from racemic S4-12 andN-diethyl enone S1-9-3 using the general procedure A. S4-13-5: (˜1:1mixture of diastereomers, light yellow foam): 1H NMR (400 MHz, CDCl₃) δ15.73 (s, 0.5H), 15.72 (s, 0.5H), 7.90 (s, 0.5H), 7.80 (s, 0.5H),7.51-7.45 (m, 4H), 7.40-7.19 (m, 11H), 5.37 (s, 2H), 5.37-5.27 (m, 2H),4.19 (t, J=8.5 Hz, 0.5H), 4.05 (d, J=10.4 Hz, 1H), 4.00 (t, J=7.9 Hz,0.5H), 3.88 (d, J=13.4 Hz, 0.5H), 3.76 (d, J=13.4 Hz, 0.5H), 3.60 (d,J=12.8 Hz, 0.5H), 3.48 (t, J=7.3 Hz, 0.5H), 3.41 (d, J=13.4 Hz, 0.5H),3.36 (t, J=8.5 Hz, 0.5H), 3.28 (d, J=15.9 Hz, 0.5H), 3.16 (d, J=12.8 Hz,0.5H), 2.93-2.73 (m, 6H), 2.54-2.46 (m, 3H), 2.37-2.31 (m, 1H),2.26-2.22 (m, 1H), 1.99-1.64 (m, 3H), 1.13-1.09 (m, 6H), 0.87 (s, 4.5H),0.86 (s, 4.5H), 0.30 (s, 1.5H), 0.29 (s, 1.5H), 0.18 (s, 1.5H), 0.17 (s,1.5H); MS (ESI) m/z 962.57 (M+H).

Compound S4-13-6 was prepared in 33% yield from S4-12 (singlediastereomer A) and azetidinyl enone S2-7-1 using general procedure A.S4-13-6 (single diastereomer A): ¹H NMR (400 MHz, CDCl₃) δ 15.94 (s,1H), 7.75 (s, 1H), 7.41-7.37 (m, 4H), 7.31-7.15 (m, 8H), 7.12-7.10 (m,3H), 5.32-5.13 (m, 4H), 3.72 (t, J=6.7 Hz, 1H), 3.56-3.51 (m, 2H), 3.40(q, J=6.7 Hz, 2H), 3.27 (q, J=6.7 Hz, 2H), 3.12 (d, J=12.8 Hz, 1H),3.05-2.97 (m, 2H), 2.69-2.59 (m, 1H), 2.47 (t, J=15.8 Hz, 1H), 2.25-2.16(m, 3H), 2.10-1.98 (m, 3H), 1.73-1.64 (m, 3H), 1.46-1.39 (m, 1H), 0.71(s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); MS (ESI) m/z 946.14 (M+H).

Compound S4-13-7 was prepared in 60% yield from S4-12 (singlediastereomer A) and pyrrolidinyl enone S2-7-2 using general procedure A.S4-13-7 (single diastereomer A): ¹H NMR (400 MHz, CDCl₃) δ 15.82 (s,1H), 7.84 (s, 1H), 7.52-7.47 (m, 4H), 7.41-7.33 (m, 5H), 7.31-7.24 (m,3H), 7.21-7.19 (m, 3H), 5.37 (s, 2H), 5.28 (s, 2H), 4.28 (d, J=11.0 Hz,1H), 3.81 (t, J=6.7 Hz, 1H), 3.64 (d, J=13.4 Hz, 1H), 3.24 (d, J=12.8Hz, 1H), 3.17-3.14 (m, 2H), 3.06-3.01 (m, 2H), 2.88-2.77 (m, 2H),2.71-2.66 (m, 2H), 2.62-2.58 (m, 1H), 2.49-2.41 (m, 1H), 2.32-2.26 (m,2H), 2.12 (d, J=14.0 Hz, 1H), 1.87-1.84 (m, 4H), 1.79-1.75 (m, 2H),1.56-1.48 (m, 1H), 0.85 (s, 9H), 0.28 (s, 3H), 0.17 (s, 3H); MS (ESI)m/z 960.18 (M+H).

Compound S13-2 was prepared in 88% yield from compound S4-13-1 by usingthe general procedure B. S4-13-2 (single diastereomer A, light yellowsolid): ¹H NMR (400 MHz, CDCl₃) δ 16.14 (s, 1H), 7.77 (s, 1H), 7.42-7.37(m, 4H), 7.30-7.21 (m, 6H), 7.18-7.15 (m, 2H), 7.12-7.08 (m, 3H), 5.30,5.26 (ABq, J=12.2 Hz, 2H), 5.21, 5.14 (ABq, J=12.2 Hz, 2H), 3.82 (br s,1H), 3.71 (t, J=7.9 Hz, 1H), 3.54 (d, J=13.4 Hz, 1H), 3.11 (d, J=13.4Hz, 1H), 3.06-3.02 (m, 1H), 2.91 (d, J=15.9 Hz, 1H), 2.63-2.50 (m, 2H),2.36 (d, J=15.3 Hz, 1H), 2.21-2.15 (m, 2H), 2.04-1.98 (m, 1H), 1.67-1.62(m, 2H), 1.46-1.38 (m, 2H), 0.64 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); MS(ESI) m/z 906.50 (M+H).

Compound S4-13-3-1 was prepared from compound S4-13-2 using generalprocedure D-2. S4-13-3-1 (single diastereomer A): ¹H NMR (400 MHz,CDCl₃) δ 16.24 (s, 1H), 7.86 (s, 1H), 7.53-7.47 (m, 4H), 7.40-7.30 (m,6H), 7.28-7.18 (m, 5H), 5.40, 5.37 (ABq, J=12.2 Hz, 2H), 5.32, 5.26(ABq, J=12.8 Hz, 2H), 3.87-3.83 (m, 2H), 3.68 (d J=13.4 Hz, 1H),3.34-3.24 (m, 2H), 2.78 (d, J=15.9 Hz, 1H), 2.69-2.62 (m, 2H), 2.48-2.42(m, 2H), 2.36-2.26 (m, 2H), 2.10-2.04 (m, 1H), 1.86-1.77 (m, 2H),1.62-1.55 (m, 1H), 1.51-1.41 (m, 1H), 0.76 (s, 9H), 0.57-0.52 (m, 2H),0.47-0.42 (m, 2H), 0.22 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 946.06(M+H).

Compound S4-14-1 was prepared from compound S4-13-2 using generalprocedure C. S4-14-1 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt) δ 7.22 (s, 1H), 4.97 (t, J=8.7 Hz, 1H), 3.90 (s,1H), 3.63-3.57 (m, 1H), 3.52-3.45 (m, 1H), 3.29-3.24 (m, 1H), 2.98-2.89(m, 1H), 2.68-2.55 (m, 3H), 2.34-2.12 (m, 4H), 1.63-1.54 (m, 1H); MS(ESI) m/z 524.24 (M+H).

Compound S4-14-2 was prepared from compound S4-13-2 using the generalprocedures D-1 (with acetaldehyde) and C. S4-14-2 (single diastereomerA): ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.22 (s, 1H), 4.96 (t,J=8.2 Hz, 1H), 3.88 (s, 1H), 3.63-3.57 (m, 1H), 3.51-3.41 (m, 2H),3.35-3.32 (m, 1H), 3.27-3.23 (m, 1H), 2.98-2.92 (m, 1H), 2.86 (d, J=13.3Hz, 1H), 2.65-2.55 (m, 2H), 2.34-2.11 (m, 4H), 1.60-1.51 (m, 1H), 1.35(t, J=7.3 Hz, 3H); MS (ESI) m z 552.26 (M+H).

Compound S4-14-3 was prepared from compound S4-13-2 using the generalprocedures D-1 (with propionaldehyde) and C. S4-14-3 (singlediastereomer A): ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.21 (s,1H), 4.96 (t, J=9.2 Hz, 1H), 3.89 (s, 1H), 3.63-3.56 (m, 1H), 3.51-3.45(m, 1H), 3.30-3.17 (m, 3H), 2.98-2.86 (m, 2H), 2.65-2.54 (m, 2H),2.33-2.11 (m, 4H), 1.82-1.72 (m, 2H), 1.61-1.51 (m, 1H), 1.02 (t, J=7.3Hz, 3H); MS (ESI) m/z 566.04 (M+H).

Compound S4-14-4 was prepared from compound S4-13-2 using the generalprocedures D-1 (with acetone) and C. S4-14-4 (single diastereomer A): ¹HNMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.21 (s, 1H), 4.96 (t, J=9.2Hz, 1H), 3.97 (s, 1 H), 3.86-3.79 (m, 1H), 3.63-3.56 (m, 1H), 3.51-3.44(m, 1H), 3.30-3.24 (m, 1H), 3.00-2.91 (m, 1H), 2.85 (d, J=12.4 Hz, 1H),2.65-2.54 (m, 2H), 2.33-2.11 (m, 4H), 1.62-1.53 (m, 1H), 1.42 (d, J=6.4Hz, 3H), 1.38 (d, J=6.4 Hz, 3H); MS (ESI) m/z 566.26 (M+H).

Compound S4-14-5-A was prepared from compound S4-13-2 by using thegeneral procedures D-1 (twice, with acetaldehyde followed byformaldehyde) and C. S4-14-5-A (single diastereomer A): ¹H NMR (400 MHz,CD₃OD, hydrochloride salt, ˜1:1 conformers) δ 7.23 (s, 1H), 4.97 (t,J=9.2 Hz, 1H), 4.25 (s, 0.5H), 4.16 (s, 0.5H), 3.64-3.57 (m, 1H),3.51-3.46 (m, 2H), 3.37-3.31 (m, 1H), 3.29-3.26 (m, 1H), 3.02-2.93 (m,5H), 2.67-2.56 (m, 2H), 2.34-2.12 (m, 4H), 1.71-1.59 (m, 1H), 1.43-1.36(m, 3H); MS (ESI) m/z 566.28 (M+H).

Compound S4-14-5-B was prepared from compound S4-13-4 using generalprocedure C and separated from compound S4-14-5-A by preparative HPLC.S4-14-5-B (single diastereomer B): ¹H NMR (400 MHz, CD₃OD, hydrochloridesalt, ˜1:1 conformers) δ 7.34 (s, 1H), 5.05 (t, J=8.2 Hz, 1H), 4.24 (s,0.5H), 4.19 (s, 0.5H), 3.65-3.59 (m, 1H), 3.52-3.46 (m, 2H), 3.36-3.31(m, 1H), 3.29-3.26 (m, 1H), 3.04-2.94 (m, 5H), 2.61-2.46 (m, 2H),2.31-2.14 (m, 4H), 1.74-1.62 (m, 1H), 1.42-1.37 (m, 3H); MS (ESI) m/z566.36 (M+H).

Compound S4-14-7 was prepared from compound S4-13-2 using generalprocedures D-1 (twice, with propionaldehyde followed by formaldehyde)and C. S4-14-7 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt, ˜1:1 conformers) δ 7.22 (s, 1H), 4.97 (t, J=9.2 Hz,1H), 4.22 (s, 0.5H), 4.15 (s, 0.5H), 3.63-3.57 (m, 1H), 3.51-3.45 (m,1H), 3.29-3.15 (m, 1H), 3.03-2.94 (m, 5H), 2.66-2.55 (m, 2H), 2.36-2.12(m, 4H), 1.87-1.73 (m, 2H), 1.68-1.59 (m, 1H), 1.05-0.98 (m, 3H); MS(ESI) m/z 580.05 (M+H).

Compound S4-14-8 was prepared from compound S4-13-2 using generalprocedures D-1 (twice, with propionaldehyde followed by acetaldehyde)and C. S4-14-8 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt, ˜1:1 conformers) δ 7.21 (s, 1H), 4.97 (t, J=9.2 Hz,1H), 4.26 (s, 0.5H), 4.23 (s, 0.5H), 3.63-3.56 (m, 2H), 3.51-3.45 (m,2H), 3.29-3.25 (m, 1H), 3.05-2.93 (m, 2H), 2.67-2.55 (m, 2H), 2.34-2.11(m, 4H), 1.88-1.78 (m, 2H), 1.68-1.59 (m, 1H), 1.41 (t, J=6.9 Hz, 3H),1.04-0.96 (m, 3H); MS (ESI) m/z 594.33 (M+H).

Compound S4-14-9 was prepared from compound S4-13-2 using generalprocedures D-1 (with excess propionaldehyde) and C. S4-14-9 (singlediastereomer A): ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.21 (s,1H), 4.96 (t, J=9.2 Hz, 1H), 4.16 (s, 1H), 3.63-3.56 (m, 1H), 3.51-3.45(m, 1H), 3.34-3.24 (m, 5H), 3.05-2.96 (m, 1H), 2.92 (d, J=12.8 Hz, 1H),2.67-2.55 (m, 2H), 2.33-2.27 (m, 1H), 2.24-2.12 (m, 3H), 1.86-1.76 (m,4H), 1.69-1.60 (m, 1H), 0.99 (t, J=7.3 Hz, 6H); MS (ESI) m/z 608.35(M+H).

Compound S4-14-10 was prepared from compound S4-13-2 using generalprocedures D-1 (twice, with acetone followed by formaldehyde) and C.S4-14-10 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD, hydrochloridesalt, ˜2:3 conformers) δ 7.22 (s, 1H), 4.96 (t, J=9.2 Hz, 1H), 4.32 (s,0.4H), 4.16-4.14 (n, 0.6H), 4.04 (0.6H), 3.83-3.80 (m, 0.4H), 3.63-3.56(m, 1H), 3.51-3.45 (m, 1H), 3.29-3.23 (m, 1H), 3.03-2.90 (m, 5H),2.67-2.55 (m, 2H), 2.36-2.12 (m, 4H), 1.68-1.53 (m, 1H), 1.44 (d, J=6.4Hz, 4H), 1.38 (d, J=6.0 Hz, 2H); MS (ESI) m/z 580.31 (M+H).

Compound S4-14-11 was prepared from compound S4-13-2 using generalprocedures D-1 (twice, with acetone followed by acetaldehyde) and C.S4-14-11 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD, hydrochloridesalt, ˜1:3 conformers) δ 7.21 (s, 1H), 4.96 (t, J=9.2 Hz, 1H), 4.32 (s,0.25H), 4.14 (m, 0.75H), 4.04-3.97 (m, 1H), 3.62-3.38 (m, 4H), 3.29-3.24(m, 1H), 3.00-2.85 (m, 2H), 2.66-2.54 (m, 2H), 2.33-2.27 (m, 2H),2.24-2.11 (m, 2H), 1.60-1.50 (m, 1H), 1.50-1.37 (m, 6.75H), 1.34 (t,J=6.9 Hz, 2.25H); MS (ESI) m/z 594.30 (M+H).

Compound S4-14-12 was prepared from compound S4-13-3-1 using generalprocedures D-1 (with formaldehyde) and C. S4-14-12 (single diastereomerA): ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.21 (s, 1H), 4.96 (t,J=9.2 Hz, 1H), 4.89-4.81 (m, 1H), 4.34 (s, 1H), 3.62-3.56 (m, 1H),3.51-3.45 (m, 1H), 3.29-3.25 (m, 1H), 3.12-3.05 (m, 5H), 2.67-2.55 (m,2H), 2.33-2.25 (m, 2H), 2.23-2.12 (m, 2H), 1.72-1.62 (m, 1H), 1.30 (brs, 1H), 1.09-0.99 (m, 3H); MS (ESI) m/z 578.07 (M+H).

Compound S4-14-13 was prepared from compound S4-13-3-1 using generalprocedures D-1 (with acetaldehyde) and C. S4-14-13 (single diastereomerA): ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.21 (s, 1H), 4.96 (t,J=9.2 Hz, 1H), 4.89-4.81 (m, 1H), 4.35 (s, 1H), 3.62-3.44 (m, 4H),3.29-3.25 (m, 1H), 3.11-3.01 (m, 2H), 2.67-2.55 (m, 2H), 2.33-2.25 (m,2H), 2.23-2.12 (m, 2H), 1.72-1.62 (m, 1H), 1.45 (t, J=7.3 Hz, 3H),1.41-1.00 (m, 3H); MS (ESI) m/z 592.11 (M+H).

Compound S4-14-14-A was prepared from compound S4-13-2 using generalprocedures D-1 (with excess acetaldehyde) and C. S4-14-14-A (singlediastereomer A): ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.21 (s,1H), 4.98 (t, J=8.7 Hz, 1H), 4.26 (s, 1H), 3.63-3.54 (m, 2H), 3.51-3.43(m, 3H), 3.34-3.26 (m, 2H), 3.04-2.92 (m, 2H), 2.67-2.55 (m, 2H),2.36-2.10 (m, 4H), 1.68-1.59 (m, 1H), 1.41 (t, J=6.9 Hz, 6H); MS (ESI)m/z 580.08 (M+H).

Compound S4-14-14-B was prepared from compound S4-13-5 using generalprocedure C and separated from compound S4-14-14 by preparative HPLC.S4-14-14-B (single diastereomer B): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt) δ 7.30 (s, 1H), 5.05 (t, J=9.2 Hz, 1H), 4.26 (s,1H), 3.63-3.58 (m, 2H), 3.52-3.46 (m, 3H), 3.37-3.31 (m, 1H), 3.29-3.26(m, 1H), 3.02-2.94 (m, 2H), 2.59 (t, J=14.6 Hz, 1H), 2.52-2.46 (m, 1H),2.31-2.18 (m, 4H), 1.69-1.60 (m, 1H), 1.42 (t, J=6.4 Hz, 6H); MS (ESI)m/z 580.37 (M+H).

Compound S4-14-16 was prepared from compound S4-13-2 using the generalprocedures D-1 (with 3-[(tert-butyldimethylsilyl)oxy]-1-propanal) and C.S4-14-16 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD, hydrochloridesalt) δ 7.20 (s, 1H), 4.96 (t, J=9.2 Hz, 1H), 3.89 (s, 1H), 3.78-3.69(m, 2H), 3.62-3.56 (m, 1H), 3.52-3.41 (m, 3H), 3.27-3.23 (m, 1H),2.99-2.91 (m, 1H), 2.85 (d, J=12.8 Hz, 1H), 2.66-2.54 (m, 2H), 2.33-2.27(m, 1H), 2.24-2.09 (m, 3H), 1.98-1.92 (m, 2H), 1.61-1.52 (m, 1H), 1.41(t, J=6.9 Hz, 6H); MS (ESI) m/z 582.05 (M+H).

Compound S4-14-17 was prepared from compound S4-13-6 using generalprocedure C. S4-14-17 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD,trifluoroacetic acid salt) δ 7.19 (s, 1H), 4.96 (t, J=8.7 Hz, 1H),4.60-4.25 (m, 4H), 4.05 (s, 1H), 3.62-3.55 (m, 1H), 3.51-3.44 (m, 1H),3.25-3.22 (m, 1H), 2.98-2.90 (m, 1H), 2.68-2.54 (m, 4H), 2.34-2.11 (m,5H), 1.60-1.50 (m, 1H); MS (ESI) m/z 564.08 (M+H).

Compound S4-14-18 was prepared from compound S4-13-7 using generalprocedure C. S4-14-18 (single diastereomer A): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt) δ 7.22 (s, 1H), 4.96 (t, J=9.2 Hz, 1H), 4.04 (s,1H), 3.63-3.57 (m, 5H), 3.51-3.47 (m, 1H), 3.26-3.22 (m, 1H), 3.01-2.94(m, 2H), 2.65-2.54 (m, 2H), 2.33-2.27 (m, 1H), 2.22-2.09 (m, 7H),1.63-1.54 (m, 1H); MS (ESI) m/z 578.11 (M+H).

The following compounds were prepared according to Scheme 5.

A solution of HNO₃ (68-70%, 0.56 mL, 8.57 mmol, 1.05 eq) in concentratedH₂SO₄ (2 mL) was added dropwise to a solution of compound S4-4-a (2.00g, 8.16 mmol, 1.0 eq) in concentrated H₂SO₄ (20 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 10 min and poured onto ice(˜200 mL). The mixture was extracted with EtOAc (150 mL). The organicphase was separated, washed with brine (2×50 mL), dried over magnesiumsulfate, filtered, and concentrated to give crude S5-1 as an orangesolid: ¹H NMR (400 MHz, CDCl₃) δ 11.5 (br s, 1H), 7.06 (s, 1H), 3.90 (s,3H), 2.32 (s, 3H); MS (ESI) m/z 288.01, 289.99 (M−H).

Compound S5-1 was dissolved in dichloromethane (16 mL). Oxalyl chloride(0.85 mL, 9.79 mmol, 1.2 eq) was added, followed by a few drops of DMF.The reaction mixture was stirred at rt for 30 min, concentrated, andfurther dried under high vacuum. The residue was re-dissolved indichloromethane (16 mL). Phenol (0.92 g, 9.79 mmol, 1.2 eq),triethylamine (2.84 mL, 20.40 mmol, 2.5 eq), and DMAP (100 mg, 0.82mmol, 0.1 eq) were added. The reaction was stirred at rt for 1 h andconcentrated under reduced pressure. The residue was dissolved in EtOAc(150 mL), washed with 1N aqueous HCl (50 mL), brine (50 mL), 1N aqueousNaOH (50 mL), and then brine (50 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated to afford the desired product S5-2as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.41 (m, 2H),7.30-7.26 (m, 1H), 7.21-7.16 (m, 2H), 7.09 (s, 1H), 3.94 (s, 3H), 2.38(s, 3H); MS (ESI) m/z 364.05, 366.06 (M−H).

A solution of BBr₃ in dichloromethane (1.0M, 8.16 mL, 8.16 mmol, 1.0 eq)was added slowly to a solution of compound S5-2 in dichloromethane (32mL) at −78° C. The reaction was stirred at −78° C. for 15 min and thenallowed to warm to 0° C. in 50 min and kept at that temperature for 10min. The reaction mixture was poured into saturated aqueous NaHCO₃solution (50 mL) and stirred at rt for 10 min. The dichloromethane wasevaporated. The residue was extracted with EtOAc (100 mL, then 30 mL).The organic extracts were combined and dried over anhydrous magnesiumsulfate. The dried solution was filtered, and the filtrate wasconcentrated to give crude S5-3 (2.20 g): ¹H NMR (400 MHz, CDCl₃) δ 11.2(br s, 1H), 7.48-7.44 (m, 2H), 7.36-7.32 (m, 1H), 7.25 (s, 1H),7.18-7.16 (m, 2H), 2.63 (s, 3H); MS (ESI) m/z 350.01, 352.03 (M−H).

Benzylbromide (0.78 mL, 6.56 mmol, 1.05 eq) and K₂CO₃ powder (1.73 g,12.50 mmol, 2.0 eq) were added to a solution of compound S5-3 (2.20 g,6.25 mmol, 1.0 eq) in acetone (12 mL). The mixture was stirred at rtovernight. The solid was filtered off and further washed with EtOAc (30mL). The filtrate was concentrated. The residue was purified by flashcolumn chromatography (2-20% EtOAc/hexanes) to afford the desiredproduct S5-4 as a white solid (1.68 g, 47% over four steps): ¹H NMR (400MHz, CDCl₃) δ 7.40-7.32 (m, 8H), 7.15 (s, 1H), 7.03-7.01 (m, 2H), 5.18(s, 2H), 2.39 (s, 3H); MS (ESI) m/z 440.09, 442.06 (M−H).

Zinc dust (12.1 g, 186 mmol) was added portionwise to a solution ofcompound S5-4 (8.24 g, 18.6 mmol) in THF (70 mL) and acetic acid (20mL). After 1 h, the reaction mixture was filtered through Celite (EtOAcwash), and the filtrate was concentrated under reduced pressure. Thematerial was diluted with EtOAc, and was washed with NaHCO₃ (saturated,aqueous solution, 3×) and brine (1×). The EtOAc layer was dried overNa₂SO₄, was filtered, and was concentrated to give 7.30 g (95%) of thecrude aniline S5-4-a as a thick oil.

A DMF (15 mL) solution of crude aniline intermediate S5-4-a (4.52 mmol),diisopropylethylamine (3.94 mL, 22.6 mmol, 5 eq) and allylbromide (1.62mL, 18.1 mmol, 4 eq) was heated in a sealed tube at 90° C. for 4 h,cooled down to rt, and diluted with EtOAc (100 mL). The organic phasewas washed with water (50 mL×2) and aqueous NH₄Cl solution (50 mL),dried over sodium sulfate, and concentrated to yield the compound S5-5:MS (ESI) m/z 492.04, 494.04 (M+H). This crude product was used directlyin the next step without further purification.

A solution of n-BuLi in hexanes (4.22 mL, 2.5M, 1.2 eq) was addeddropwise to a solution of compound S5-5 (4.33 g, 8.8 mmol, 1 eq) in THF(30 mL) at −78 OC under a N₂ atmosphere. The resulting red solution wasstirred at −78° C. for 5 min and then DMF (2.04 mL, 3 eq) was addeddropwise. The reaction was slowly warmed to 0° C. in 1 h. Saturatedaqueous NH₄Cl was added. The resulting mixture was extracted three timeswith EtOAc. The combined EtOAc extracts were washed with brine, dried(sodium sulfate), and concentrated. Purification of the residue by flashchromatography (5% to 15%, EtOAc/hexane) gave compound S5-6 (1.92 g,50%): ¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 7.44-7.30 (m, 8H),7.25-7.22 (m, 1H), 7.21 (d, J=6.8 Hz, 2H), 5.86-5.75 (m, 2H), 5.14 (s,2H), 5.15-5.06 (m, 4H), 3.73 (d, J=6.4 Hz, 4H), 2.41 (s, 3H) MS (ESI)m/z 440.14 (M−H).

Compound S5-6 (577 mg, 1.31 mmol, 1 eq) was dissolved in 6 mL dry DMF.Sarcosine (202 mg, 1.5 eq) was added. The resulting suspension washeated to 80° C. for 4 h until it became a homogeneous dark yellowsolution. The reaction solution was cooled down to rt, diluted withethyl acetate, washed with water and brine, dried (sodium sulfate), andconcentrated to afford compound S5-7 (727 mg, crude): ¹H NMR (400 MHz,CDCl₃) δ 7.48-7.19 (m, 10H), 6.66 (s, 1H), 6.02-5.86 (m, 1H), 5.36-4.99(m, 4H), 3.35 (s, 2H), 3.19-2.78 (m, 3H), 2.42-2.31 (m, 3H), 2.35 (s,3H), 2 24 (s, 3H), 2.09-1.95 (m, 1H), 1.70-1.50 (m, 1H); MS (ESI) m/z469.15 (M+H).

To a solution of compound S5-7 (727 mg, crude 1.3 mmol, 1 eq) in 6 mLdry DCM was added tetrakis(triphenylphosphine) palladium (75 mg, 0.05eq) and 1,3-dimethylbarbituric acid (609 mg, 3 eq) under nitrogen. Thereaction mixture was purged with nitrogen, stirred at rt for 2 h, dilutewith 25 mL saturated aqueous NaHCO₃ solution, and extracted with DCM (25mL×3). The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and concentrated to yield the aniline intermediateS5-7-a (crude): MS (ESI) m/z 429.10 (M+H).

Formaldehyde (290 μL, 37% aqueous solution, 3 eq), sodiumtriacetoxyborohydride (551 mg, 2 eq), and acetic acid (223 μL, 3 eq)were added sequentially to a solution of intermediate S5-7-a indichloromethane (5 mL) at 25° C. After stirring for 30 min, the reactionmixture was quenched by the addition of saturated aqueous sodiumbicarbonate (15 mL) and extracted with dichloromethane (3×10 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. Purification of the residue by flashchromatography (15% to 50%, EtOAc/hexane) gave compound S5-8-1 (441 mg,41% for 3 steps): ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.40-7.32(m, 5H), 7.28-7.20 (m, 1H), 7.19-7.13 (m, 2H), 6.68 (s, 1H), 5.15 (s,2H), 3.12-3.00 (m, 2H), 2.92-2.81 (m, 2H), 2.66 (s, 3H), 2.54-2.46 (m,1H), 2.41 (s, 3H), 2.36 (s, 3H), 2.33-2.22 (m, 1H), 2.12-2.00 (m, 1H),1.45-1.32 (m, 1H); MS (ESI) m/z 443.16 (M+H).

Compound S5-9-5 was prepared in 50% yield from S5-8-1 and N-diallylenone S1-9-2 using general procedure A. S5-9-5 (˜1:1 mixture ofdiastereomers, yellow foam): 1H NMR (400 MHz, CDCl₃) δ 15.90 (br s, 1H),7.42-7.18 (m, 10H), 6.59 (s, 0.5H), 6.53 (s, 0.5H), 5.75-5.67 (m, 2H),5.27 (s, 2H), 5.13-4.96 (m, 6H), 4.06 (d, J=10.4 Hz, 1H), 3.31-3.08 (m,6H), 3.02-2.92 (m, 2H), 2.80-2.69 (m, 4H), 2.48-2.28 (m, 6H), 2.22-2.14(m, 1H), 2.09-2.03 (m, 4H), 1.53-1.48 (m, 1H), 0.722 (s, 4.5H), 0.718(s, 4.5H), 0.163 (s, 1.5H), 0.156 (s, 1.5H), 0.026 (s, 3H); MS (ESI) m/z883.56 (M+H).

Compound S5-9-1 was prepared in 95% yield from compound S5-9-5 usinggeneral procedure B. S5-9-1 (mixture of diastereomers): MS (ESI) m/z803.48 (M+H).

Compound S5-10-1 was prepared from compound S5-9-1 using generalprocedure C, and the two diastereomers were separated by preparativeHPLC.

S5-10-1-A: 1H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.17 (s, 1H),4.70 (d, J=6.0 Hz, 1H), 3.91 (s, 1H), 3.88-3.81 (m, 1H), 3.64-3.38 (m,4H), 3.19-3.05 (m, 8H), 2.70-2.47 (m, 3H), 2.34-2.24 (m, 1H), 2.03-1.96(m, 1H), 1.66-1.57 (m, 1H); MS (ESI) m/z 511.30 (M+H).

S5-10-1-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.12 (s, 1H),4.56 (d, J=6.0 Hz, 1H), 3.91 (s, 1H), 3.84-3.78 (m, 1H), 3.43-3.34 (m,4H), 3.29-3.25 (m, 1H), 3.14 (s, 3H), 2.98-2.90 (m, 1H), 2.83 (s, 3H),2.69-2.60 (m, 2H), 2.42 (t, J=14.6 Hz, 1H), 2.28-2.24 (m, 1H), 1.91-1.84(m, 1H), 1.69-1.59 (n, 1H); MS (ESI) m/z 511.30 (M+H).

Compound S5-10-2 was prepared from compound S5-9-1 using generalprocedures D-1 (with acetaldehyde) and C, and the two diastereomers wereseparated preparative HPLC.

S5-10-2-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.16 (s, 1H),4.68 (d, J=5.5 Hz, 1H), 3.89 (s, 1H), 3.86-3.80 (m, 1H), 3.54-3.52 (m,1H), 3.48-3.33 (m, 5H), 3.17-3.07 (m, 8H), 2.86 (d, J=12.8 Hz, 1H),2.68-2.62 (m, 1H), 2.47 (t, J=14.6 Hz, 1H), 2.33-2.30 (m, 1H), 2.00-1.93(m, 1H), 1.64-1.55 (m, 1H), 1.36 (t, J=6.9 Hz, 3H); MS (ESI) m/z 539.33(M+H).

S5-10-2-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.16 (s, 1H),4.61 (d, J=5.9 Hz, 1H), 3.91 (s, 1H), 3.87-3.80 (m, 1H), 3.49-3.32 (m,7H), 3.15 (s, 3H), 3.03-2.94 (m, 1H), 2.91 (s, 3H), 2.85 (d, J=12.4 Hz,1H), 2.71-2.62 (m, 1H), 2.45 (t, J=14.2 Hz, 1H), 2.28-2.24 (m, 1H),1.94-1.88 (m, 1H), 1.67-1.58 (m, 1H), 1.36 (t, J=7.3 Hz, 3H); MS (ESI)m/z 539.33 (M+H).

Compound S5-10-3 was prepared from compound S5-9-1 using generalprocedures D-1 (twice, with acetaldehyde followed by formaldehyde) andC, and the two diastereomers were separated by preparative HPLC.

S5-10-3-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers)δ 7.15 (s, 1H), 4.67 (br s, 1H), 4.26 (s, 0.5H), 4.17 (s, 0.5H),3.86-3.79 (m, 1H), 3.54-3.37 (m, 7H), 3.18-2.94 (m, 11H), 2.67-2.62 (m,1H), 2.46 (t, J=14.2 Hz, 1H), 2.34 (br t, J=11.0 Hz, 1H), 1.99-1.92 (m,1H), 1.72-1.61 (m, 1H), 1.45-1.37 (m, 3H); MS (ESI) m/z 553.34 (M+H).

S5-10-3-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers)δ 7.12 (s, 1H), 4.56 (d, J=5.5 Hz, 1H), 4.25 (s, 0.5H), 4.16 (s, 0.5H),3.85-3.78 (m, 1H), 3.53-3.26 (m, 7H), 3.14 (s, 3H), 3.02-2.94 (m, 5H),2.82 (s, 3H), 2.68-2.59 (m, 1H), 2.40 (t, J=14.6 Hz, 1H), 2.29-2.22 (m,1H), 1.91-1.84 (m, 1H), 1.75-1.63 (m, 1H), 1.44-1.36 (m, 3H); MS (ESI)m/z 553.34 (M+H).

To a solution of S5-8-1 (1.63 g, 3.67 mmol, 1 eq) in MeOH (18 mL), wasadded palladium on carbon (Degussa, 10 wt %, 161 mg). An atmosphere ofhydrogen was introduced and the reaction mixture was stirred at roomtemperature. After 30 min, the hydrogen balloon had deflated, so anotherportion of palladium catalyst (50 mg) was added, followed byreintroduction of hydrogen atmosphere. After an additional hour, thereaction mixture was filtered through a small Celite pad and thefiltrate was concentrated under reduced pressure to give intermediateS5-8-2. To a solution of the above crude oil S5-8-2 in dichloromethane(20 mL) was added di-tert-butyl dicarbonate (890 mg, 4.08 mmol, 1.1 eq)and dimethylaminopyridine (54 mg, 0.44 mmol, 0.1 eq), and the reactionmixture was stirred at ambient temperature. After 50 min, the mixturewas concentrated under reduced pressure. Purification of the resultingresidue via flash column chromatography (Biotage, 50 g silica gelcolumn, 20% to 90% acetonitrile in dichloromethane gradient) provided animpure fraction containing desired product. A second purification viaflash column chromatography (Biotage, 50 g silica gel column, 2% to 70%acetonitrile in dichloromethane gradient) provided the desired compoundS5-8-3 (1.57 g, 94%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.45-7.39 (m, 2H), 7.30-7.22 (m, 3H), 6.97 (s, 1H), 3.14-3.07 (m, 2H),2.94-2.87 (m, 2H), 2.70 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 2.30 (q,J=9.2 Hz, 1H), 2.13-2.02 (m, 1H), 1.44 (s, 9H), 1.43-1.34 (m, 1H); MS(ESI) m/z 453.99 (M−H).

Compound S5-9-4 was prepared in 75% yield from S5-8-3 and N-diethylenone S1-9-3 using general procedure A. S5-9-4 (yellow foam, ˜1:1diastereomers): MS (ESI) m/z 869.92 (M+H).

Compound S5-10-4 was prepared from compound S5-9-4 using generalprocedure C, and the two diastereomers were separated by preparativeHPLC.

S5-10-4-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.26 (s, 1H),4.83 (d, J=5.5 Hz, 1H), 4.30 (s, 1H), 3.92-3.85 (m, 1H), 3.82-3.71 (m,2H), 3.62-3.56 (m, 3H), 3.53-3.42 (m, 3H), 3.38-3.32 (m, 1H), 3.32 (s,3H), 3.20 (s, 3H), 3.11 (d, J=15.1 Hz, 1H), 2.96 (d, J=13.3 Hz, 1H),2.74-2.55 (m, 2H), 2.42-2.39 (m, 1H), 2.05-1.98 (m, 1H), 1.71-1.62 (m,1H), 1.43 (t, J=7.3 Hz, 3H), 1.41 (t, J=7.3 Hz, 3H); MS (ESI) m/z 567.53(M+H).

S5-10-4-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.28 (s, 1H),4.78 (d, J=5.5 Hz, 1H), 4.31 (s, 1H), 3.93-3.80 (m, 2H), 3.72-3.68 (m,1H), 3.62-3.46 (m, 6H), 3.38-3.30 (m, 1H), 3.21-3.14 (m, 1H), 3.16 (s,3H), 3.14 (s, 3H), 2.96 (d, J=12.8 Hz, 1H), 2.78-2.66 (m, 1H), 2.58 (t,J=14.2 Hz, 1H), 2.32-2.29 (m, 1H), 2.02-1.95 (m, 1H), 1.75-1.65 (m, 1H),1.414 (t, J=7.3 Hz, 3H), 1.409 (t, J=7.3 Hz, 3H); MS (ESI) m/z 567.53(M+H).

The following compounds were prepared according to Scheme 6.

Compound S5-4-a (crude) was dissolved in methyl acrylate (10 mL) andacetic acid (20 mL) and was heated to 110° C. in a sealed vessel. Afterstirring overnight, additional methyl acrylate (5 mL) was added, andheating was continued at 110° C. overnight. Upon cooling to rt, thereaction mixture was concentrated. The material was dissolved in EtOAcand was washed with NaHCO₃ (saturated, aqueous solution, 3×) and brine(1×). The EtOAc layer was dried over Na₂SO₄, was filtered, and wasconcentrated to give the corresponding aniline intermediate. Thisintermediate was dissolved in CH₂Cl₂ (100 mL) and acetic acid (5 mL) andformaldehyde (37%, aqueous, 5 mL) were added. Na(OAc)₃BH (5.6 g, 26.4mmol) was then added. After 1 h, the reaction mixture was quenched withNaHCO₃ (saturated, aqueous solution) and the layers were separated. Theorganic layer was washed with NaHCO₃ (saturated, aqueous solution, 2×)and brine (1×), was dried over Na₂SO₄, was filtered, and wasconcentrated. The material was purified by column chromatography (100 gBiotage column, 0 to 12% EtOAc in hexanes gradient) to give 3.94 g (44%,3 steps) of the product S6-1: R_(f)=0.20 in 10% EtOAc/hexanes: ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.32 (m, 7H), 7.26-7.21 (m, 1H), 7.11-7.04 (m,3H), 5.10 (s, 2H), 3.66 (s, 3H), 3.48-3.41 (m, 2H), 2.80 (s, 3H), 2.50(dt, J=6.9 Hz, 2.3 Hz, 2H), 2.38 (s, 3H); MS (ESI) m/z 512.33, 514.33(M+H).

n-BuLi (2.5M solution, 5.2 mL, 13.0 mmol) was added dropwise to a −78°C. solution of S6-1 (3.94 g, 7.69 mmol) in THF (30 mL). After 5 min, thereaction was quenched with NH₄Cl (saturated, aqueous solution) and wasextracted with EtOAc (2×). The combined extracts were dried over Na₂SO₄,were filtered, and were concentrated. The material was purified bycolumn chromatography (100 g Biotage column, 5 to 30% EtOAc in hexanesgradient) to give 0.854 g (28%) of the product S6-2 as a bright yellowoil: ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.45-7.41 (m, 2H),7.38-7.30 (m, 5H), 7.26-7.22 (m, 1H), 7.10-7.06 (m, 2H), 5.15 (s, 2H),3.55 (t, J=6.4 Hz, 2H), 2.87 (s, 3H), 2.77 (t, J=6.4 Hz, 2H), 2.41 (s,3H); MS (ESI) m/z 402.00 (M+H).

Ti(OEt)₄ (3.82 mL, 18.40 mmol) was added to a solution of compound S6-2(2.46 g, 6.12 mmol) and (S)-(−)-t-butylsulfinamide (2.23 g, 18.40 mmol)in toluene (20 mL), and the reaction mixture was heated to 75° C. Afterstirring overnight, the reaction mixture was diluted with EtOAc and wasquenched with NaHCO₃ (saturated, aqueous solution). The mixture wasfiltered through Celite (EtOAc wash), and the filtrate was washed withNaHCO₃ (saturated, aqueous solution, 3×) and brine. The organics weredried over Na₂SO₄, were filtered, and were concentrated. The materialwas purified by column chromatography (100 g Biotage column, 15 to 60%EtOAc in hexanes gradient) to give 1.943 g (63%) of the sulfinimineintermediate as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H),7.43-7.22 (m, 8H), 7.14-7.08 (m, 2H), 5.14 (s, 2H), 3.47-3.37 (m, 1H),3.36-3.30 (m, 2H), 3.08-2.99 (m, 1H), 2.75 (s, 3H), 2.38 (s, 3H), 1.27(s, 9H); MS (ESI) m/z 505.16 (M+H).

L-Selectride (1.0M solution in THF, 19.30 mL, 19.30 mmol) was addeddropwise to a 0° C. solution of the above sulfinimine (1.94 g, 3.85mmol) in THF (20 mL). After complete addition, the ice bath was removed,and the reaction mixture was stirred for 4 h. The reaction mixture wasquenched with NaHCO₃ (saturated, aqueous solution) and was diluted withEtOAc. The mixture was washed with NaHCO₃ (saturated, aqueous solution,3×) and brine. The organics were dried over Na₂SO₄, were filtered, andwere concentrated. The material was purified by column chromatography(50 g Biotage column, 40 to 100% EtOAc in hexanes gradient) to give 1.65g (85%) of the desired sulfonamide S6-3 (single diastereomer A) as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.26 (m, 7H), 7.24-7.19 (m,1H), 7.12-7.07 (m, 2H), 6.86 (s, 1H), 5.07 (ABq, J=15.6 Hz, 11.9 Hz,2H), 4.42-4.34 (m, 1H), 3.38 (d, J=10.1 Hz, 1H), 3.18-3.12 (m, 2H), 2.65(s, 3H), 2.37 (s, 3H), 2.36-2.25 (m, 1H), 2.13-2.03 (m, 1H), 1.21 (s,9H); MS (ESI) m/z 507.19 (M+H).

The above sulfonamide S6-3 (1.65 g, 3.27 mmol) was stirred in HCl (4Msolution in 1,4-dioxane, 4 mL) and MeOH (16 mL). After 1 h, the reactionmixture was concentrated and was re-dissolved in CH₂Cl₂ (25 mL).Na(OAc)₃BH (2.08 g, 9.80 mmol) and formaldehyde (37% aqueous solution, 5mL) were added. After 15 min, the reaction mixture was quenched withNaHCO₃ (saturated, aqueous solution) and was diluted with EtOAc. Themixture was washed with NaHCO₃ (saturated, aqueous solution, 3×) andbrine. The organics were dried over Na₂SO₄, were filtered, and wereconcentrated. The material was purified by column chromatography (50 gBiotage column, 50 to 100% EtOAc in hexanes gradient) to give 1.33 g(94%) of single enantiomer S6-4 (single enantiomer A) as a solid:R_(f)=0.26 in 5% MeOH/CH₂Cl₂; ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.41 (m,2H), 7.37-7.18 (m, 7 H), 7.12-7.06 (m, 2H), 5.10 (s, 2H), 3.79 (dd,J=9.2 Hz, 6.9 Hz, 1H), 3.16-3.10 (m, 2H), 2.62 (s, 3H), 2.37 (s, 3H),2.24 (s, 6H), 2.12-2.02 (m, 1H), 1.56-1.68 (m, 1H); MS (ESI) m/z 431.34(M+H).

Compound S6-5-4 was prepared in 57% yield from S6-4 and N-diallyl enoneS1-9-2 using general procedure A. S6-5-4 (single diastereomer, yellowfoamy solid): ¹H NMR (400 MHz, CDCl₃) δ 15.90 (br s, 1H), 7.41-7.36 (m,4H), 7.29-7.14 (m, 7H), 5.77-5.67 (m, 2H), 5.27 (s, 2H), 5.13-4.96 (m,6H), 4.07 (d, J=10.4 Hz, 1H), 3.57 (br s, 1H), 3.26-3.01 (m, 6H),2.94-2.88 (m, 1H), 2.82-2.76 (m, 1H), 2.50 (s, 3H), 2.47-2.28 (m, 3H),2.17-2.03 (m, 7H), 1.88-1.76 (m, 2H), 0.72 (s, 9H), 0.16 (s, 3H), 0.04(s, 3H); MS (ESI) m/z 871.56 (M+H).

Compound S6-5-1 was prepared in 79% yield from compound S6-5-4 usinggeneral procedure B. S6-5-1 (single diastereomer): ¹H NMR (400 MHz,CDCl₃) δ 16.57 (br s, 1H), 7.66-7.61 (m, 1H), 7.54-7.51 (m, 2H),7.47-7.42 (m, 2H), 7.36-7.26 (m, 6H), 5.38, 5.34 (ABq, J=12.2 Hz, 2H),5.22, 5.12 (ABq, J=12.2 Hz, 2H), 3.92 (d, J=2.4 Hz, 1H), 3.67 (t, J=5.5Hz, 1H), 3.14-2.93 (m, 2H), 2.72-2.66 (m, 1H), 2.60-2.57 (m, 1H), 2.48(s, 3H), 2.38-2.21 (m, 7H), 2.14-2.04 (m, 2H), 1.96-1.84 (m, 2H),1.57-1.48 (m, 1H), 0.73 (s, 9H), 0.20 (s, 3H), 0.10 (s, 3H); MS (ESI)m/z 791.48 (M+H).

Compound S6-6-1 was prepared from compound S6-5-1 using generalprocedure C.

S6-6-1 (single diastereomer): ¹H NMR (400 MHz, CD₃OD, hydrochloridesalt) δ 7.34 (s, 1H), 5.01 (d, J=6.0 Hz, 1H), 3.92 (s, 1H), 3.74-3.67(m, 1H), 3.64-3.58 (m, 1H), 3.29-3.26 (m, 1H), 3.15-3.06 (m, 7H), 2.76(br s, 3H), 2.69-2.64 (m, 3H), 2.53 (t, J=14.6 Hz, 1H), 2.35-2.30 (m,1H), 1.68-1.59 (m, 1H); MS (ESI) m/z 499.32 (M+H).

Compound S6-6-2 was prepared from compound S6-5-1 using generalprocedures D-1 (with acetaldehyde) and C. S6-6-2 (single diastereomer):¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.33 (s, 1H), 4.99 (d,J=6.9 Hz, 1H), 3.91 (s, 1H), 3.71-3.65 (m, 1H), 3.62-3.56 (m, 1H),3.46-3.40 (m, 1H), 3.38-3.32 (m, 1H), 3.30-3.25 (m, 1H), 3.12-3.09 (m,7H), 2.86 (d, J=12.8 Hz, 1H), 2.76 (br s, 3H), 2.66-2.61 (m, 2H), 2.50(t, J=14.6 Hz, 1H), 2.33-2.30 (m, 1H), 1.66-1.57 (m, 1H), 1.36 (t, J=6.9Hz, 3H); MS (ESI) m/z 527.28 (M+H).

Compound S6-6-3 was prepared from compound S6-5-1 using generalprocedures D-1 (twice, with acetaldehyde followed by formaldehyde) andC. S6-6-3 (single diastereomer): ¹H NMR (400 MHz, CD₃OD, hydrochloridesalt, ˜1:1 conformers) δ 7.30 (s, 1H), 4.98 (t, J=6.4 Hz, 1H), 4.26 (s,0.5H), 4.17 (s, 0.5H), 3.65-3.50 (m, 3H), 3.37-3.30 (m, 2H), 3.09-2.94(m, 11H), 2.75 (br s, 3H), 2.63-2.58 (m, 2H), 2.49 (t, J=14.2 Hz, 1H),2.35-2.29 (m, 1H), 1.74-1.63 (m, 1H), 1.44-1.37 (m, 3H); MS (ESI) m/z541.35 (M+H).

The following compounds were prepared according to Scheme 7.

To p-trifluoromethoxyanisole (S7-1, 19.20 g, 0.10 mol, 1 eq) inmethylene chloride (200 mL) at 0° C. was added a pre-cooled (0° C.)solution of nitric acid (14.29 mL, 69%, 0.22 mol, 2.2 eq) in sulfuricacid (17.86 mL) dropwise within 15 min. The reaction was stirred from 0°C. to rt for overnight. The aqueous layer was removed. The organic layerwas washed with saturated aqueous sodium bicarbonate (100 mL×2) andbrine (100 mL×1), dried over sodium sulfate, and concentrated to drynessto yield the desired compound S7-2 as a pale liquid (24.20 g,quantitative): R_(f)=0.45 (20% EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ7.75 (d, J=2.4 Hz, 1H), 7.42 (dd, J=3.0, 9.2 Hz, 1H), 7.10 (d, J=9.2 Hz,1H), 3.97 (s, 3H).

To a solution of compound S7-2 (0.10 mol, 1 eq) in THF (600 mL) at 0° C.was added a solution of Na₂S₂O₄ (102.4 g, 85%, 0.50 mol, 5 eq) in water(400 mL). The reaction was stirred at rt for 16 h. The organic layer wascollected. The aqueous later was extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over sodium sulfate and concentrated.EtOAc (200 mL) was added to the residue. The insoluble material wasfiltered. The filtrate was collected. Aqueous HCl (150 mL, 2N) andmethanol (150 mL) were added to the solid. The mixture was stirred at rtfor 2 h, neutralized with aqueous NaOH (6N), and extracted with EtOAc(100 mL×3). The extracts were combined with the previously saved EtOAcfiltrate, dried over sodium sulfate, and concentrated to dryness toyield the desired product S7-3 as a deep yellow liquid (16.69 g, 81%):R_(f)=0.50 (20% EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ 6.70 (d, J=9.2Hz, 1H), 6.59 (s, 1H), 6.57 (d, J=9.2 Hz, 1H), 3.83 (s, 3H); MS (ESI)m/z 208.0 (M+H).

To compound S7-3 (16.69 g, 0.081 mol, 1 eq) in methylene chloride (250mL) at 0° C. was added pridine-HBr₃ (31.09 g, 0.097 mol, 1.2 eq) insmall portions. The reaction mixture was stirred at 0° C. for 1 h,washed with aqueous Na₂S₂O₃ (1M, 100 mL×3) and brine (100 mL×1), driedover sodium sulfate, and concentrated. Flash column chromatography onslica gel with 0% to 20% EtOAc/hexane gave the desired product S7-4 as apale liquid (21.30 g, 92%): R_(f)=0.30 (20% EtOAc/hexane): ¹H NMR (400MHz, CDCl₃) δ 6.90 (s, 1H), 6.66 (d, J=1.2 Hz, 1H), 4.01 (br s, 2H),3.83 (s, 3H); MS (ESI) m/z 286.0 (M+H).

To compound S7-4 (19.84 g, 69.58 mmol, 1 eq) in dioxane (70 mL) andaqueous HCl (70 mL, 8.5N) at 0° C. was added a solution of NaNO₂ (5.26g, 76.23 mmol, 1.1 eq) in water (28 mL) slowly. The reaction mixture wasstirred at rt for 30 min and added slowly into a stirred solution of KI(115.50 g, 0.70 mol, 10 eq) in water (140 mL) at 0° C. (gas evolution!).The reaction mixture was stirred at rt for 72 h and extracted with EtOAc(200 mL×1, 50 mL×2). The extracts were combined and concentrated. Theresidue was re-dissolved in EtOAc (100 mL). The solution was washed withaqueous Na₂SO₃ (2M, 100 mL×2), saturated aqueous sodium bicarbonate (100mL×1), and brine (100 mL×1), dried over sodium sulfate, andconcentrated. Flash column chromatography on slica gel with 0% to 5%EtOAc/hexane afforded the desired compound S7-5 as a colorless liquid(19.80 g, 72%): R_(f)=0.66 (10% EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ7.67 (s, 1H), 6.99 (s, 1H), 3.87 (s, 3H).

A solution of compound S7-5 (18.80 g, 47.36 mmol, 1 eq) in THF (100 mL)was cooled to −78° C. and added with iPrMgCl—LiCl (43.72 mL, 1.3M inTHF, 56.84 mmol, 1.2 eq) dropwise within 30 min. The reaction wasstirred at −78° C. for 30 min. Dry carbon dioxide was bubbled throughthe reaction mixture at −78° C. for 30 min. The reaction mixture wasstirred from −78° C. to rt for 2 h, added with aqueous HCl (1N, 100 mL),and concentrated. The aqueous mixture was extracted with EtOAc (50mL×4). The combined extracts were dried over sodium sulfate andconcentrated to dryness to yield the desired product S7-6 as a palesolid (15.37 g, quantitative): MS (ESI) m/z 312.9 (M−H).

To compound S7-6 (crude, 47.36 mmol, 1 eq) in methylene chloride (100mL) at 0° C. was added DMF (0.10 mL, 1.30 mmol, 0.027 eq) and oxalylchloride (19.64 mL, 122.00 mmol, 2.5 eq) dropwise (gas evolution). Thereaction was stirred at rt for 1.5 h and concentrated to dryness. Theresidue was redissolved in methylene chloride (100 mL). Phenol (5.51 g,58.55 mmol, 1.2 eq), DIEA (12.67 mL, 72.74 mmol, 1.5 eq), and DMAP (0.60g, 4.91 mmol, 0.10 eq) were added. The reaction solution was stirred atrt for overnight and concentrated. The residue was redissolved in EtOAc.The solution was washed with saturated aqueous sodium bicarbonate (50mL×2) and brine (50 mL×1), dried over sodium sulfate, and concentratedto dryness. Flash column chromatography on slica gel with 0% to 20%EtOAc/hexane gave the desired product S7-7 as a colorless oil (17.00 g,90%): R_(f)=0.33 (10% EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d,J=1.2 Hz, 1H), 7.45-7.37 (m, 2H), 7.29-7.16 (m, 4H), 3.86 (s, 3H); MS(ESI) m/z 391.0 (M+H).

s-Bu₂NH (14.64 mL, 84.85 mmol, 2 eq) and Et₃N—HCl (146 mg, 1.06 mmol,0.025 eq) were dissolved in anhydrous THF (150 mL) and cooled to −78° C.n-BuLi (34.00 mL, 2.5M in hexane, 85.00 mmol, 2 eq) was added dropwise.The solution was stirred at 0° C. for 10 min and recolled to −78° C.TMEDA (12.75 mL, 85.00 mmol, 2 eq) was added, followed by the dropwiseaddition of compound S7-7 (16.61 g, 42.47 mmol, 1 eq) in THF (100 mL)over 30 min. The reaction was stirred at −78° C. for 1 h. Methyl iodide(18.50 mL, 0.30 mol, 7 eq) was added rapidly over one min. The reactionwas stirred from −78° C. to rt for 2 h, added with saturated aqueousammonium chloride (200 mL), and concentrated. The aqueous solution wasextracted with EtOAc (100 mL×3). The combined extracts were dried oversodium sulfate and concentrated. Flash column chromatography on slicagel with 0% to 10% EtOAc/hexane yielded the desired product S7-8 as apale oil (11.76 g, 69%): R_(f)=0.60 (20% EtOAc/hexane): ¹H NMR (400 MHz,CDCl₃) δ 7.48-7.41 (m, 2H), 7.32-7.25 (m, 1H), 7.23 (d, J=7.3 Hz, 2H),7.10 (s, 1H), 3.91 (s, 3H), 2.44 (s, 3H); MS (ESI) m/z 402.9 (M−H).

To compound S7-8 (12.26 g, 30.26 mmol, 1 eq) in methylene chloride (60mL) at −78° C. was added BBr₃ (33.30 mL, 1.0M in methylene chloride,33.30 mmol, 1.1 eq) dropwise. The reaction was stirred from −78° C. to0° C. for 1 h. Saturated aqueous sodium bicarbonte (200 mL) was added.The mixture was stirred at rt for 15 min and extracted with methylenechloride (50 mL×4). The combined extracts were dried over sodium sulfateand concentrated to yield the crude phenol intermediate S7-8-a as a paleoil (12.00 g, quantitative): R_(f)=0.70 (20% EtOAc/hexane): ¹H NMR (400MHz, CDCl₃) δ 10.97 (s, 1H), 7.50-7.44 (m, 2H), 7.38-7.30 (m, 1H),7.25-7.15 (m, 3H), 2.68 (s, 3H); MS (ESI) m/z 388.9 (M−H).

The above crude phenol S7-8-a (30.26 mmol, 1 eq) was dissolved in DMF(30 mL). Potassium carbonate (8.35 g, 60.50 mmol, 2 eq) andbenzylbromide (4.31 mL, 36.28 mmol, 1.2 eq) were added. The reactionmixture was stirred at rt for 1 h, diluted with EtOAc (300 mL), washedwith water (600 mL×1, 100 mL×1) and brine (100 mL×1), dried over sodiumsulfate, and concentrated. Flash column chromatography on slica gel with0% to 10% EtOAc/hexane afforded the desired product S7-9 as a whitesolid (13.20 g, 91% over two steps): R_(f)=0.70 (20% EtOAc/hexane): ¹HNMR (400 MHz, CDCl₃) δ 7.43-7.20 (m, 8H), 7.16 (s, 1H), 7.03 (d, J=9.1Hz, 2H), 5.12 (s, 2H), 2.43 (s, 3H); MS (ESI) m/z 479.0 (M−H).

To compound S7-9 (4.81 g, 10.00 mmol, 1 eq) in THF at 0° C. was addediPrMgCl—LiCl (11.54 mL, 1.3M in THF, 15.00 mmol, 1.5 eq) dropwise over10 min. The reaction was stirred at 0° C. for 2 h and cooled to −78° C.N-Boc pyrrolidinone (3.41 mL, 20.00 mmol, 2 eq) was added. The reactionwas warmed from −78° C. to rt over 1 h with stirring. Saturated aqueousammonium chloride (200 mL) was added. The mixture was extracted withEtOAc (100 mL×1, 50 mL×2). The combined EtOAc extracts were dried oversodium sulfate and concentrated under reduced pressure. Flash columnchromatography on silica gel with 0-15% EtOAc/hexane yielded the desiredproduct S7-10 as a white solid (3.20 g, 56%): R_(f) 0.40 (20%EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ 7.47.45-7.30 (m, 6H), 7.28-7.20(m, 1H), 7.08-7.02 (m, 3H), 6.87 (s, 1H), 5.14 (s, 2H), 4.00 (br t,J=8.9 Hz, 2H), 2.63 (dt, J=2.5, 9.2 Hz, 2H), 2.40 (s, 3H), 1.30-1.10 (m,2H); MS (ESI) m/z 588.2, (M−H).

To compound S7-10 (3.25 g, 5.53 mmol, 1 eq) in methylene chloride (5 mL)at 0° C. was added TFA-methylene chloride (10 mL, 1:1, v/v). Thereaction solution was stirred at rt for 30 min and concentrated todryness under reduced pressure. Saturated aqueous sodium bicarbonate(100 mL) was added to the residue. The mixture was extracted withmethylene chloride (50 mL×4). The combined methylene chloride extractswere dried over sodium sulfate and concentrated under reduced pressureto yield the cyclic imine intermediate as a pale oil (2.73 g): ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.20 (m, 9H), 7.06 (d, J=10.3 Hz, 2H), 5.17 (s,2H), 4.03 (t, J=7.4 Hz, 2H), 2.92 (t, J=8.0 Hz, 2H), 2.44 (s, 3H),2.11-2.00 (n, 2H); MS (ESI) m/z 470.0 (M+H).

The above intermediate was redissolved in methanol (40 mL) and cooled to0° C. Sodium borohydride (1.05 g, 27.76 mmol, 5 eq) was added. Thereaction was stirred at rt for 30 min. Additional sodium borohydride(1.00 g×2) was added. The reaction was stirred at rt for 30 min. AqueousHCl (2N) was added until pH=2-3. Saturated aqueous sodium bicarbonate(100 mL) was added. The mixture was extracted with methylene chloride(50 mL×4). The combined methylene chloride extracts were dried oversodium sulfate and concentrated to yield S7-11 as a pale oil (2.71 g,crude): MS (ESI) m/z 472.1 (M+H).

To a solution of compound S7-11 (crude product of the previous steps,0.87 mmol, 1 eq) in DCM (3 mL) was added PhCHO (106 μL, 1.044 mmol, 1.2eq), HOAc (100 μL, 1.74 mmol, 2.0 eq) and STAB (369 mg, 1.74 mmol, 2.0eq). The resulting reaction mixture was stirred at rt for 1 h and 25min. Then saturated aq. NaHCO₃ was added. The resulting mixture wasextracted with DCM (20 mL, then 10 mL). The combined organic phase wasdried over Na₂SO₄, filtered and concentrated under reduced pressure.Flash chromatography on silica gel using 2%→10% EtOAc/hexanes yieldedthe desired product S7-12 (272 mg, 56% over 3 steps) as a white solid:¹H NMR (400 MHz, CDCl₃) δ 7.49-7.46 (m, 3H), 7.41-7.35 (m, 5H),7.32-7.24 (m, 6H), 7.11-7.10 (m, 2H), 5.22, 5.18 (ABq, J=11.6 Hz, 2H),3.84 (t, J=8.5 Hz, 1H), 3.77 (d, J=13.4 Hz, 1H), 3.17-3.10 (m, 2H), 2.43(s, 3H), 2.31-2.24 (m, 2H), 1.91-1.80 (m, 2H), 1.64-1.55 (m, 1H); MS(ESI) m/z 562.23 (M+H).

Compound S7-13-4 was prepared in 88% yield from S7-12 and N-diallylenone S1-9-2 using general procedure A. S7-13-4 (mixture ofdiastereomers, yellow foam): ¹H NMR (400 MHz, CDCl₃, ˜1:1 diastereomers)δ 16.02 (s, 0.5H), 16.00 (s, 0.5H), 7.56-7.14 (m, 11H), 5.86-5.76 (m,2H), 5.38 (s, 2H), 5.28-5.20 (m, 4H), 5.12 (d, J=10.4 Hz, 2H), 3.88-3.76(m, 2H), 3.59 (d, J=12.8 Hz, 1H), 3.36-3.08 (m, 7H), 2.99-2.88 (m, 1H),2.75-2.64 (m, 1H), 2.55-2.45 (m, 2H), 2.35-2.24 (m, 2H), 2.15 (d, J=14.0Hz, 1H), 1.92-1.79 (m, 2H), 1.64-1.58 (m, 1H), 0.86 (s, 4.5H), 0.85 (s,4.5), 0.28 (s, 3H), 0.16 (s, 3H); MS (ESI) m/z 1002.49 (M+H).

Compound S7-13-1 was prepared from compound S7-13-4 using generalprocedure B and the two diastereomers were separated by preparative HPLCon a C-18 column.

S7-13-1-A (47%, early eluting diastereomer A): ¹H NMR (400 MHz, CDCl₃) δ16.28 (br s, 1H), 7.62-7.60 (m, 1H), 7.38-7.16 (m, 9H), 5.52 (br s, 2H),5.30, 5.26 (ABq, J=12.2 Hz, 2H), 4.26 (br s, 1H), 4.05-3.86 (m, 3H),2.79-2.71 (m, 2H), 2.60-2.57 (m, 2H), 2.40-2.02 (m, 7H), 1.47-1.28 (m,1H), 0.66 (s, 9H), 0.14 (s, 3H), 0.00 (s, 3H); MS (ESI) m/z 922.43(M+H).

S7-13-1-B (39%, later eluting diastereomer B): ¹H NMR (400 MHz, CDCl₃) δ16.29 (br s, 1H), 7.53 (s, 1H), 7.44-7.42 (m, 2H), 7.36-7.35 (m, 2H),7.29-7.11 (m, 4H), 7.08-7.06 (m, 2H), 5.52 (br s, 2H), 5.30-5.11 (m,4H), 4.05-3.98 (m, 1H), 3.83 (d, J=13.4 Hz, 1H), 3.62 (d, J=13.4 Hz,1H), 3.54 (t, J=8.5 Hz, 1H), 2.82 (dd, J=3.7, 15.3 Hz, 1H), 2.69-2.58(m, 2H), 2.51-2.48 (m, 1H), 2.29-2.24 (m, 1H), 2.16-2.00 (m, 3H),1.89-1.84 (3H), 1.42-1.32 (m, 1H), 0.64 (s, 9H), 0.13 (s, 3H), 0.00 (s,3H); MS (ESI) m/z 922.43 (M+H).

Compounds S7-14-1-A and S7-14-1-B were prepared from the correspondingcompounds S7-13-1-A and S7-13-1-B separately using general procedure C.

S7-14-1-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.20 (s, 1H),4.91-4.83 (m, 1H), 3.90 (s, 1H), 3.52-3.46 (m, 2H), 3.20 (dd, J=4.1,15.6 Hz, 1H), 3.01-2.92 (m, 1H), 2.54-2.48 (m, 1H), 2.68-2.65 (m, 1H),2.40 (t, J=14.6 Hz, 1H), 2.35-2.18 (m, 4H), 1.64-1.55 (m, 1H); MS (ESI)m/z 540.17 (M+H).

S7-14-1-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.17 (s, 1H),4.91 (t, J=9.6 Hz, 1H), 3.89 (s, 1H), 3.59-3.47 (m, 2H), 3.18 (dd,J=4.1, 15.6 Hz, 1H), 3.01-2.92 (m, 1H), 2.68-2.64 (m, 1H), 2.59-2.52 (m,1H), 2.40 (t, J=14.6 Hz, 1H), 2.34-2.06 (m, 4H), 1.64-1.54 (m, 1H); MS(ESI) m/z 540.18 (M+H).

Compound S7-14-2-A was prepared from compound S7-13-1-A using generalprocedures D-1 (with acetaldehyde) and C. S7-14-2-A: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt) δ 7.19 (s, 1H), 4.89-4.85 (m, 1H), 3.88 (s,1H), 3.52-3.39 (m, 3H), 3.38-3.32 (m, 1H), 3.19 (dd, J=4.1, 16.0 Hz,1H), 3.01-2.93 (m, 1H), 2.87-2.84 (m, 1H), 2.54-2.48 (m, 1H), 2.40 (t,J=14.6 Hz, 1H), 2.34-2.16 (m, 4H), 1.63-1.54 (m, 1H), 1.36 (t, J=7.3 Hz,3H); MS (ESI) m/z 568.18 (M+H).

Compound S7-14-3-A was prepared from compound S7-13-1-A using generalprocedures D-1 (twice, with acetaldehyde followed by formaldehyde) andC. S7-14-3-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1conformers) δ 7.20 (s, 1H), 4.91-4.85 (m, 1H), 4.24 (s, 0.5H), 4.15 (s,0.5H), 3.54-3.44 (m, 3H), 3.38-3.33 (m, 1H), 3.22-3.19 (m, 1H),3.05-2.93 (m, 5H), 2.54-2.48 (m, 1H), 2.40 (t, J=14.6 Hz, 1H), 2.35-2.16(m, 4H), 1.72-1.60 (m, 1H), 1.44-1.36 (m, 3H); MS (ESI) m/z 582.21(M+H).

The following compounds were prepared according to Scheme 8.

To a solution of bromide S7-9 (500 mg, 1.04 mmol, 1 eq) in THF (5 mL)was added Turbo Grignard solution (1.3M in THF, 1.04 mL, 1.35 mmol, 1.3eq) dropwise at ˜−3° C. The resulting reaction solution was stirred at0° C. for 1 h, then cooled to −78° C. A solution of DMF (160 μL, 2.08mmol, 2.0 eq) in THF (0.6 mL) was added dropwise at below −73° C. Theresulting reaction mixture was allowed to warm up to rt slowly over 1 hand 40 min. Saturated aqueous NH₄Cl was added, and the resultingreaction mixture was extracted with EtOAc (50 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product S8-1 (503 mg), MS (ESI) m/z 429.16 (M−H), was useddirectly for the next reaction without further purification.

To a solution of the above crude product S8-1 (260 mg, 0.537 mmol, 1 eq)in DCE (2 mL) was added pyrrolidine (67 μL, 0.806 mmol, 1.5 eq), HOAc(92 μL, 1.61 mmol, 3.0 eq) and STAB (228 mg, 1.07 mmol, 2.0 eq). Theresulting reaction mixture was stirred at rt for 30 min. Then saturatedaq. NaHCO₃ was added. The resulting mixture was extracted with DCM (3×15mL). The combined organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Flash chromatography on silica gelusing 1%→30% EtOAc/hexanes yielded the desired product S8-2 (236 mg, 90%over 2 steps) as a white solid: MS (ESI) m/z 486.27 (M+H).

Compound S8-3-4 was prepared in 89% yield from S8-2 and N-diallyl enoneS1-9-2 using general procedure A. S8-3-4 (yellow solid): ¹H NMR (400MHz, CDCl₃) δ 16.00 (s, 1H), 7.52-7.50 (m, 2H), 7.46-7.44 (m, 2H),7.40-7.31 (m, 5H), 7.26-7.24 (m, 2H), 5.84-5.74 (m, 2H), 5.38 (s, 2H),5.29, 5.24 (ABq, J=12.8 Hz, 2H), 5.21 (d, J=18.6 Hz, 2H), 5.10 (d,J=10.4 Hz, 2H), 3.71, 3.62 (ABq, J=15.3 Hz, 2H), 3.36-3.32 (m, 2H),3.23-3.11 (m, 3H), 2.96-2.90 (m, 1H), 2.69 (t, J=15.3 Hz, 1H), 2.54-2.40(m, 7H), 2.14 (d, J=14.0 Hz, 1H), 1.73-1.76 (m, 4H), 0.84 (s, 9H), 0.28(s, 3H), 0.15 (s, 3H); MS (ESI) m/z 926.56 (M+H).

Compound S8-3-1 was prepared in 86% yield from compound S8-3-4 usinggeneral procedure B. S8-3-1: ¹H NMR (400 MHz, CDCl₃) δ 16.44 (s, 1H),7.44-7.37 (m, 4H), 7.29-7.18 (m, 6H), 7.15 (br s, 1H), 5.30, 5.26 (ABq,J=12.2 Hz, 2H), 5.22, 5.14 (ABq, J=12.8 Hz, 2H), 3.82 (br s, 1H), 3.55(s, 2H), 2.91 (dd, J=3.7, 15.9 Hz, 1H), 2.69-2.61 (m, 1H), 2.52 (d,J=12.2 Hz, 1H), 2.32 (br s, 4H), 2.14 (t, J=15.3 Hz, 1H), 2.02-1.99 (m,1H), 1.65 (br s, 4H), 1.46-1.38 (m, 1H), 0.64 (s, 9H), 0.12 (s, 3H),0.00 (s, 3H); MS (ESI) m/z 846.49 (M+H).

Compound S8-4-1 was prepared from compound S8-3-1 using generalprocedure E. S8-4-1: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.27(s, 1H), 4.52 (s, 2H), 3.91 (s, 1H), 3.68-3.62 (m, 1H), 3.58-3.52 (m,1H), 3.27-3.13 (m, 3H), 3.04-2.95 (m, 1H), 2.70-2.66 (m, 1H), 2.40 (t,J=14.6 Hz, 1H), 2.28-2.17 (m, 3H), 2.07-2.04 (m, 2H), 1.64-1.55 (m, 1H);MS (ESI) m/z 554.19 (M+H).

Compound S8-4-2 was prepared from compound S8-4-1 using generalprocedures D-1 (with acetaldehyde) and E. S8-4-2: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt) δ 7.25 (s, 1H), 4.51 (s, 2H), 3.88 (s, 1H),3.66-3.60 (m, 1H), 3.57-3.52 (m, 1H), 3.46-3.42 (m, 1H), 3.38-3.33 (m,1H), 3.26-3.12 (m, 3H), 3.05-2.96 (m, 1H), 2.88-2.85 (m, 1H), 2.40 (t,J=15.1 Hz, 1H), 2.27-2.16 (m, 3H), 2.09-2.02 (m, 2H), 1.63-1.53 (m, 1H),1.36 (t, J=7.3 Hz, 3H); MS (ESI) m/z 582.23 (M+H).

Compound S8-4-3 was prepared from compound S8-4-1 using generalprocedures D (twice, with acetaldehyde followed formaldehyde) and E.S8-4-3: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers) δ7.27 (s, 1H), 4.52 (s, 2H), 4.25 (s, 0.5H), 4.16 (s, 0.5H), 3.68-3.62(m, 1H), 3.58-3.45 (m, 2H), 3.38-3.33 (m, 1H), 3.27-3.11 (m, 3H),3.08-2.94 (m, 5H), 2.40 (t, J=14.6 Hz, 1H), 2.30-2.18 (m, 3H), 2.10-2.03(m, 2H), 1.71-1.60 (m, 1H), 1.44-1.37 (n, 3H); MS (ESI) m/z 596.24(M+H).

The following compounds were prepared according to Scheme 9.

To diisopropylamine (36 μL, 0.25 mmol, 2.5 eq) in THF at −78° C. wasadded n-BuLi (0.16 mL, 1.6M/hexanes, 0.25 mmol, 2.5 eq) drop-wise. Thereaction solution was stirred at 0° C. for 10 min and cooled to −78° C.TMEDA (39 μL, 0.26 mmol, 2.6 eq) was added, followed by the addition ofa THF solution (3 mL) of compound S9-1 (133 mg, 0.25 mmol, 2.5 eq,WO2010126607) drop-wise over 5 min. The reaction solution was stirred at−78° C. for 30 min. Compound S2-7-1 (45 mg, 0.10 mmol, 1 eq,⁴R^(4′)RN=azetidinyl, in 2 mL THF) was added drop-wise. The reactionsolution was stirred from −78° C. to 0° C. for 1 h, added with saturatedaqueous sodium bicarbonate (50 mL), and extracted with EtOAc (50 mL×3).The EtOAc extracts were combined, dried over sodium sulfate, andconcentrated. The residue was purified by column chromatography onsilica gel with 0%-8% EtOAc-hexane to yield the desired product S9-2-1as a yellow solid (43 mg, 51%): ¹H NMR (400 MHz, CDCl₃) δ 16.44 (s, 1H),7.60-7.10 (m, 20H), 6.64 (d, J=10.4 Hz, 1H), 5.39 (d, J=12.2 Hz, 1H),5.35 (d, J=12.2 Hz, 1H), 5.20 (d, J=9.8 Hz, 1H), 5.07 (d, J=9.9 Hz, 1H),4.33 (d, J=14.6 Hz, 2H), 4.20 (d, J=14.6 Hz, 2H), 3.61 (d, J=6.1 Hz,1H), 3.55-3.45 (m, 2H), 3.40-3.32 (m, 2H), 3.01 (dd, J=4.4, 15.2 Hz,1H), 2.85-2.75 (m, 1H), 2.35-1.55 (m, 6H), 0.80 (s, 9H), 0.15 (s, 6H);MS (ESI) m/z 932.5 (M+H).

To a THF solution (1.5 mL) of compound S9-2-1 (43 mg, 0.046 mmol) in apolypropylene vial was added 48% aqueous HF (0.5 mL). The reactionsolution was stirred at rt for 2 h and added into aqueous K₂HPO₄ (5 g in20 mL water) with stirring. The mixture was extracted with EtOAc (20mL×3). The EtOAc extracts were combined, dried over sodium sulfate, andconcentrated to yield compound S9-3-1 as an orange solid: MS (ESI) m/z818.5 (M+H).

Compound S9-3-1 (0.046 mmol, 1 eq) was dissolved in methanol-dioxane (4mL, 7:1, v/v). HCl (1 mL, 0.5N in methanol) and 10% Pd—C (11 mg, 0.005mmol, 0.1 eq) were added. The reaction mixture was purged with hydrogenand stirred under a hydrogen atmosphere (1 atm) for 2 h. The catalystwas filtered off with a Celite pad and washed with methanol (2 mL×3).The filtrate was concentrated. The residue was purified by preparativeHPLC on a PolymerX column with 0%-35% acetonitrile-0.05N aqueous HClover 20 min to yield the desired compound S9-4-1 as a yellow solid (15mg, 61%): MS (ESI) m/z 460.2 (M+H). The sample contained a small amountof ring-opened product S9-4-3: MS (ESI) m/z 496.3 (M+H).

Compound S9-4-1 (15 mg, 0.028 mmol, 1 eq) was dissolved inacetonitrile-DMPU (1 mL, 1:3, v/v). Pyrrolidinylacetyl chloride (6 mg,HCl salt, 0.032 mmol, 1.2 eq) was added. The reaction solution wasstirred at rt for 1 h and added into dithyl ether (50 mL) with rapidstirring. The precipitate was collected on a small Celite pad, washedwith more dithyl ether (5 mL×4), and eluted with methanol (5 mL×3). Themethanol eluent was collected and concentrated. The residue was purifiedby preparative HPLC on a PolymerX column with 0%-35% acetonitrile-0.05Naqueous HCl over 20 min to yield the desired product S9-5-1 as a yellowsolid (5 mg, bis-HCl salt, 31%): ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d,J=11.0 Hz, 1H); 4.64-4.54 (m, 2H), 4.34 (s, 2H), 4.27-4.15 (m, 2H), 4.12(s, 1H), 3.83-3.75 (m, 2H), 3.55-2.50 (m, 6H), 2.40-2.00 (m, 6H),1.60-1.48 (m, 1H); MS (ESI) m/z 571.2 (M+H).

Compound S9-5-3 was isolated from the preparation of compound S9-5-1 asa yellow solid (2 mg, bis-HCl salt): ¹H NMR (400 MHz, CD₃OD) δ 8.23 (d,J=11.0 Hz, 1H), 4.31 (s, 2H), 3.90 (s, 1H), 3.82-3.74 (m, 2H), 3.71 (t,J=6.1 Hz, 2H), 3.55-2.80 (m, 7H), 2.31-2.00 (m, 8H), 1.64-1.50 (m, 1H);MS (ESI) m/z 607.2 (M+H).

Using similar procedures, compound S9-5-2 was prepared from D-ringprecursor S9-1 and enone S2-7-2 as a yellow solid (bis-HCl salt): ¹H NMR(400 MHz, CD₃OD) δ 8.23 (d, J=10.4 Hz, 1H), 4.32 (s, 2H), 4.00 (s, 1H),3.98-3.65 (m, 4H), 3.50-2.95 (m, 7H), 2.45-1.95 (m, 10H), 1.68-1.55 (m,1H); MS (ESI) m/z 585.3 (M+H).

The following compounds were prepared from a fully assembled D-ringprecursor and N-di-allyl enone S1-9-2 using general procedures A, B,D-1, and E.

S9-5-4: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 8.22 (d, J=11.0Hz, 1H), 4.33 (s, 2H), 3.89 (s, 1H), 3.82-3.76 (m, 2H), 3.23-3.12 (m,3H), 3.02-2.94 (m, 1H), 2.67-2.64 (m, 1H), 2.32-2.14 (m, 4H), 2.12-2.02(m, 2H), 1.63-1.54 (m, 1H); MS (ESI) m/z 531.31 (M+H).

S9-5-5: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 8.22 (d, J=11.0Hz, 1H), 4.33 (s, 2H), 3.87 (s, 1H), 3.82-3.76 (m, 2H), 3.47-3.32 (m,2H), 3.24-3.11 (m, 3H), 3.04-2.97 (m, 1H), 2.86-2.82 (m, 1H), 2.31-2.14(m, 4H), 2.12-2.03 (m, 2H), 1.62-1.52 (m, 1H), 1.36 (t, J=7.3 Hz, 3H);MS (ESI) m/z 559.27 (M+H).

S9-5-6: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers) δ8.23 (d, J=11.0 Hz, 1H), 4.32 (s, 2H), 4.22 (s, 0.5H), 4.13 (s, 0.5H),3.82-3.76 (m, 2H), 3.50-3.46 (m, 1H), 3.37-3.30 (m, 1H), 3.23-3.13 (m,3H), 3.06-2.93 (m, 5H), 2.32-2.14 (m, 4H), 2.12-2.06 (m, 2H), 1.70-1.59(m, 1H), 1.43-1.36 (m, 3H); MS (ESI) m/z 573.33 (M+H).

The following compounds were prepared according to Scheme 10.

Compound S10-2 was synthesized from S10-1 (prepared using literatureprocedures including WO 2010129057) according the similar proceduresused for the preparation of S4-12. Compound S10-2: ¹H NMR (400 MHz,CDCl₃) δ 7.47-7.45 (m, 2H), 7.38-7.31 (m, 5H), 7.26-7.22 (m, 1H), 7.20(br s, 1H), 7.12-7.09 (m, 2H), 5.16 (s, 2H), 3.70 (s, 3H), 3.64 (t,J=7.9 Hz, 1H), 3.39 (t, J=7.9 Hz, 1H), 2.64-2.55 (m, 1H), 2.39 (s, 3H),2.28-2.17 (m, 2H), 2.11-2.03 (m, 1H), 1.93-1.83 (m, 2H), 1.64-1.55 (m,1H), 1.03 (t, J=7.3 Hz, 3H); MS (ESI) m/z 446.42 (M+H).

Compound S10-3-4 was prepared in 68% yield from S10-2 and N-diallylenone S1-9-2 using general procedure A. S10-3-4 (single diastereomer):¹H NMR (400 MHz, CDCl₃) δ 16.16 (s, 1H), 7.51-7.46 (m, 4H), 7.40-7.21(m, 7H), 5.86-5.76 (m, 2H), 5.36 (s, 2H), 5.23-5.07 (m, 6H), 4.12 (d,J=9.7 Hz, 1H), 3.66 (s, 3H), 3.68-3.61 (m, 1H), 3.35-3.33 (m, 3H),3.24-3.14 (m, 3H), 2.96-2.90 (m, 1H), 2.61 (t, J=15.3 Hz, 1H), 2.52-2.40(m, 3H), 2.25-2.11 (m, 4H), 1.94-1.82 (m, 2H), 1.62-1.54 (m, 1H), 0.98(t, J=7.3 Hz, 3H), 0.82 (s, 9H), 0.26 (s, 3H), 0.13 (s, 3H); MS (ESI)m/z 886.60 (M+H).

Compound S10-3-1 was prepared in 78% yield from compound S10-3-4 usinggeneral procedure B. S10-3-1 (single diastereomer)¹H NMR (400 MHz,CDCl₃) δ 16.54 (s, 1H), 7.42-7.41 (m, 2H), 7.37-7.34 (m, 2H), 7.27-7.15(m, 7H), 5.29, 5.25 (ABq, J=12.2 Hz, 2H), 5.16, 5.07 (ABq, J=12.2 Hz,2H), 3.82 (br s, 1H), 3.61 (t, J=8.5 Hz, 1H), 3.48 (s, 3H), 3.32-3.28(m, 1H), 2.95 (dd, J=4.3, 15.3 Hz, 1H), 2.69-2.59 (m, 1H), 2.52-2.43 (m,2H), 2.18-1.98 (m, 5H), 1.88-1.73 (m, 2H), 1.56-1.38 (m, 2H), 0.90 (t,J=7.3 Hz, 3H), 0.63 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); MS (ESI) m/z806.51 (M+H).

Compound S10-4-1 was prepared from compound S10-3-1 using generalprocedure C. S10-4-1 (single diastereomer): ¹H NMR (400 MHz, CD₃OD,hydrochloride salt) δ 7.09 (s, 1H), 3.90 (s, 1H), 3.86-3.80 (m, 1H),3.68 (s, 3H), 3.37-3.30 (m, 1H), 3.28-3.07 (m, 3H), 3.00-2.91 (m, 1H),2.67-2.54 (m, 2H), 2.41 (t, J=14.2 Hz, 1H), 2.34-2.21 (m, 5H), 1.66-1.57(m, 1H), 1.25 (t, J=7.3 Hz, 3H); MS (ESI) m/z 514.28 (M+H).

Compound S10-4-2 was prepared from compound S10-3-1 using generalprocedures D-1 (with acetaldehyde) and C. S10-4-2 (single diastereomer):¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.10 (s, 1H), 3.88 (s,1H), 3.85-3.80 (m, 1H), 3.68 (s, 3H), 3.46-3.31 (m, 3H), 3.27-3.07 (m,3H), 3.01-2.92 (m, 1H), 2.86-2.83 (m, 1H), 2.62-2.55 (m, 1H), 2.39 (t,J=14.2 Hz, 1H), 2.34-2.22 (m, 5H), 1.64-1.55 (m, 1H), 1.36 (t, J=7.3 Hz,3H), 1.25 (t, J=7.3 Hz, 3H); MS (ESI) m/z 542.35 (M+H).

Compound S10-4-3 was prepared from compound S10-3-1 using generalprocedures D-1 (twice, with acetaldehyde followed by formaldehyde) andC. S10-4-3 (single diastereomer): 1H NMR (400 MHz, CD₃OD, hydrochloridesalt, ˜1:1 conformers) δ 7.11 (s, 1H), 4.24 (s, 0.5H), 4.14 (s, 0.5H),3.86-3.80 (m, 1H), 3.69 (s, 3H), 3.53-3.47 (m, 1H), 3.38-3.30 (m, 2H),3.29-3.07 (m, 3H), 3.02-2.94 (m, 5H), 2.62-2.57 (m, 1H), 2.40 (t, J=15.1Hz, 1H), 2.34-2.24 (m, 5H), 1.73-1.61 (m, 1H), 1.44-1.37 (m, 3H), 1.25(t, J=7.3 Hz, 3H); MS (ESI) m/z 556.37 (M+H).

The following compounds were prepared according to Scheme 11.

Compound S11-2-4 was synthesized in 71% yield from S11-1 (preparedaccording to literature procedures including WO 2011123536) andN-diallyl enone S1-9-2 using general procedure A. S11-2-4: ¹H NMR (400MHz, CDCl₃) δ 16.00 (s, 1H), 7.51-7.49 (m, 2H), 7.40-7.31 (m, 8H),5.86-5.76 (m, 2H), 5.37 (s, 2H), 5.22 (d, J=17.1 Hz, 2H), 4.12 (d, J=9.8Hz, 2H), 4.90 (s, 2H), 4.13-4.03 (m, 3H), 3.93-3.80 (m, 2H), 3.34-3.12(m, 5H), 3.02-2.96 (m, 1H), 2.62 (t, J=15.3 Hz, 1H), 2.55-2.41 (m, 2H),2.14 (d, J=14.6 Hz, 1H), 1.12 (s, 9H), 0.82 (s, 9H), 0.26 (s, 3H), 0.12(s, 3H); MS (ESI) m/z 874.57 (M+H).

Compound S11-2-1 was prepared in 44% yield from compound S11-2-4 usinggeneral procedure B. S11-2-1: ¹H NMR (400 MHz, CDCl₃) δ 16.45 (s, 1H),7.39-7.33 (m, 4H), 7.30-7.23 (m, 6H), 7.16 (s, 1H), 5.30, 5.26 (ABq,J=12.2 Hz, 2H), 4.98, 4.84 (ABq, J=11.0 Hz, 2H), 4.03 (br s, 2H), 3.84(br s, 3H), 2.95-2.91 (m, 1H), 2.72-2.64 (m, 1H), 2.53-2.51 (m, 1H),2.14-2.02 (m, 2H), 1.50-1.42 (m, 1H), 1.04 (s, 9H), 0.65 (s, 9H), 0.11(s, 3H), 0.00 (s, 3H); MS (ESI) m/z 794.49 (M+H).

Compound S11-3-1 was prepared from compound S11-2-1 using generalprocedure C. S11-3-1: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.87(s, 2H), 4.74 (s, 2H), 3.88 (s, 1H), 3.20-3.16 (m, 1H), 3.03-2.97 (m,1H), 2.65 (d, J=12.4 Hz, 1H), 2.33 (t, J=14.6 Hz, 1H), 2.26-2.22 (m,1H), 1.64-1.54 (m, 1H), 1.52 (s, 9H); MS (ESI) m/z 502.27 (M+H).

Compound S11-3-2 was prepared from compound S11-2-1 using generalprocedures D-1 (with acetaldehyde) and C. S11-3-2: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt) δ 4.87 (s, 2H), 4.74 (s, 2H), 3.86 (s, 1H),3.47-3.30 (m, 2H), 3.19-3.15 (m, 1H), 3.05-2.98 (m, 1H), 2.84 (d, J=12.8Hz, 1H), 2.32 (t, J=15.1 Hz, 1H), 2.25-2.21 (m, 1H), 1.62-1.52 (m, 1H),1.52 (s, 9H), 1.36 (t, J=6.9 Hz, 3H); MS (ESI) m/z 530.28 (M+H).

Compound S11-3-3 was prepared from compound S11-2-1 using generalprocedure D-1 (twice, with acetaldehyde followed by formaldehyde) and C.S11-3-3: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers) δ4.87 (s, 2H), 4.75 (s, 2H), 4.22 (s, 0.5H), 4.13 (s, 0.5H), 3.52-3.44(m, 1H), 3.38-3.30 (m, 1H), 3.22-3.18 (m, 1H), 3.11-2.93 (m, 5H),2.36-2.21 (m, 2H), 1.70-1.59 (m, 1H), 1.52 (s, 9H), 1.43-1.36 (m, 3H);MS (ESI) m/z 544.33 (M+H).

The following compounds were prepared according to Scheme 12.

To phenol S7-8-a (5.20 mmol, 1 eq, obtained from treatment of 2.50 g ofthe corresponding benzyl ether with TFA/anisole, containing inseparableimpurities, ˜75% pure) in toluene (20 mL) at rt was added NaH (0.83 g,20.80 mmol, 60% in mineral oil, 4 eq) in small portions. The mixture wasstirred at rt for 20 min. Iodine (5.28 g, 20.80 mmol, 4 eq) was added.The reaction mixture was stirred at rt overnight, diluted with EtOAc(200 mL), washed with 1N aqueous HCl (100 mL×1), 5% aqueous Na₂S₂O₃ (100mL×2), and brine (100 mL×1), dried over sodium sulfate, and concentratedunder reduced pressure to yield the crude product S12-1 as a pale oil:R_(f) 0.45 (10% EtOAc/hexane); MS (ESI) m/z 514.8 (M−H).

To the above crude phenol S12-1 (5.20 mmol, 1 eq) in DMF (10 mL) at rtwas added potassium carbonate (1.44 g, 10.44 mmol, 2 eq) and benzylbromide (0.74 mL, 6.23 mmol, 1.2 eq). The reaction mixture was stirredat rt for 3 h, diluted with EtOAc (200 mL), washed with water (200 mL×1,100 mL×1) and brine (50 mL×1), dried over sodium sulfate, andconcentrated under reduced pressure. Flash column chromatography onsilica gel with 0-3% EtOAc/hexane yielded the desired product S12-2 as apale oil (3.48 g): R_(f) 0.55 (10% EtOAc/hexane): ¹H NMR (400 MHz,CDCl₃) δ 7.55-7.00 (m, 10H), 5.11 (s, 2H), 2.44 (s, 3H); MS (ESI) m/z604.8 (M−H).

To compound S12-2 (5.20 mmol, 90% pure) was added cesium carbonate (2.54g, 7.80 mmol, 1.5 eq), BocNH₂ (0.67 g, 5.70 mmol, 1.1 eq), Xantphos(1.20 g, 2.07 mmol, 0.4 eq), Pd(OAc)₂ (224 mg, 1.00 mmol, 0.2 eq), andanhydrous dioxane (10 mL). Nitrogen gas was bubbled through the mixturefor 5 min. The reaction vessel was sealed and heated at 80° C. for 48 hwith vigorous stirring. After cooling down to rt, water (100 mL) wasadded. The reaction mixture was extracted with methylene chloride (100mL×1, 50 mL×2). The combined extracts were dried over sodium sulfate andconcentrated under reduced pressure. Flash column chromatography onsilica gel with 0-15% EtOAc/hexane yielded the desired product S12-3 asa white solid (0.87 g, 28% overall yield): R_(f) 0.25 (10%EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.20 (m, 8H), 7.03 (d,J=7.3 Hz, 2H), 6.07 (br s, 1H), 5.03 (s, 2H), 2.46 (s, 3H), 1.46 (s,9H); MS (ESI) m/z 594.0 (M−H).

To compound S12-3 (0.68 g, 1.14 mmol, 1 eq) in anhydrous THF (6 mL) at−78° C. was added PhLi (0.95 mL, 1.80M/nBu₂O, 1.71 mmol, 1.5 eq)dropwise over 1 min. After stirring at −78° C. for 10 min, nBuLi (0.86mL, 1.60M/hexane, 1.38 mmol, 1.2 eq) was added dropwise over 2 min. Thereaction was stirred at −78° C. for 5 min. Dry DMF (0.26 mL, 3.36 mmol,3 eq) was added dropwise. The reaction was stirred from −78° C. to 0° C.over 1 h and quenched with saturated aqueous sodium bicarbonate (50 mL).The reaction mixture was extracted with methylene chloride (50 mL×3).The combined extracts were dried over sodium sulfate and concentratedunder reduced pressure. Flash column chromatography on silica gel with0-15% EtOAc/hexane yielded the desired product S12-4 as a pale solid(232 mg, 37%): R_(f)0.33 (10% EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ10.21 (s, 1H), 7.90 (br s, 1H), 7.45-7.20 (m, 8H), 7.05 (d, J=7.3 Hz,2H), 5.00 (s, 2H), 2.42 (s, 3H), 1.43 (s, 9H); MS (ESI) m/z 544.2 (M−H).Note: use of reduced amounts of PhLi and n-BuLi can potentially increaseproduct yield.

To compound S12-4 (232 mg, 0.43 mmol, 1 eq) in dry DMF (2 mL) at rt wasadded NaH (21 mg, 60% in mineral oil, 0.52 mmol, 1.2 eq). After stirringat rt for 30 min, allyl bromide (56 μL, 0.64 mmol, 1.5 eq) was added.The reaction mixture was stirred at rt for 1 h, diluted with EtOAc (50mL), washed with water (50 mL×2) and brine (50 mL×1), dried over sodiumsulfate, and concentrated under reduced pressure. Flash columnchromatography on silica gel with 0-8% EtOAc/hexane yielded the desiredproduct S12-5 as a pale oil (206 mg, 82%): R_(f) 0.45 (10%EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1H), 7.40-6.95 (m,10H), 5.95-5.75 (m, 1H), 5.10-4.85 (m, 4H), 4.64, 4.28 (dd, dd, J=5.5,12.8 Hz, J=4.9, 12.2 Hz, 1H), 4.00, 3.89 (dd, dd, J=8.1, 10.2 Hz, J=8.6,12.8 Hz, 1H), 2.46, 2.43 (s, s, 3H), 1.53, 1.50 (s, s, 9H); MS (ESI) m/z584.2 (M−H).

To compound S12-5 (206 mg, 0.35 mmol) in DMF (2 mL) was added N-methylglycine (47 mg, 0.53 mmol, 1.5 eq). The mixture was heated at 100° C.for 24 h. After cooling down to rt, the reaction mixture was dilutedwith EtOAc (50 mL), washed with aqueous saturated sodium bicarbonate (50mL×2) and brine (50 mL×1), dried over sodium sulfate, and concentratedunder reduced pressure. Flash column chromatography on silica gel with0-15% EtOAc/hexane yielded the desired product S12-6-1 as a white foam(190 mg, 89%): R_(f) 0.50 (10% EtOAc/hexane): ¹H NMR (400 MHz, CDCl₃),broad and complex due to presence of various rotamers and/or conformers:MS (ESI) m z 613.3 (M+H).

Compound S12-6-2 was prepared similarly from S12-5 and N-benzyl glycine:¹H NMR (400 MHz, CDCl₃), broad and complex due to presence of variousrotamers and/or conformers: MS (ESI) m/z 689.3 (M+H).

Compound S12-7-1 was prepared from S12-6-1 and N-diallyl enone S1-9-2using general procedure A and the two diastereomers were separated.

S12-7-1-A (52% yield, less polar diastereomer on TLC, rotamers): MS(ESI) m/z 1053.55 (M+H).

S12-7-1-B (18% yield, more polar diastereomer on TLC, rotamers): MS(ESI) m/z 1053.55 (M+H).

Compound S12-7-2 was prepared from S12-6-2 and N-diallyl enone S1-9-2using general procedure A and the two diastereomers were separated.

S12-7-2-A (52% yield, less polar diastereomer on TLC, rotamers): MS(ESI) m/z 1129.58 (M+H).

S12-7-2-B (18% yield, more polar diastereomer on TLC, rotamers): MS(ESI) m/z 1129.58 (M+H).

Compounds S12-7-3-A and S12-7-3-B were prepared from the correspondingcompounds S12-7-1-A and S12-7-1-B separately using general procedure B.

S12-7-3-A (92% yield, rotamers): MS (ESI) m/z 973.54 (M+H).

S12-7-3-B (42% yield, rotamers): MS (ESI) m/z 973.51 (M+H).

Compounds S12-7-4-A and S12-7-4-B were prepared from the correspondingcompounds S12-7-2-A and S12-7-2-B separately using general procedure B.

S12-7-4-A (54% yield, rotamers): MS (ESI) m/z 1049.60 (M+H).

S12-7-4-B (25% yield, rotamers): MS (ESI) m/z 1049.61 (M+H).

A mixture of Pd(dba)₂ (5.6 mg, 0.0097 mmol, 0.1 eq) and DPPB (4.1 mg,0.0097 mmol, 0.1 eq) was dissolved in THF (1 mL). The resulting reactionsolution was stirred at rt under nitrogen for 10 min, and added to asolution of compound S12-7-1-A (102 mg, 0.097 mmol, 1 eq) and2-mercaptobenzoic acid (19.4 mg, 0.126 mmol, 1.3 eq) in THF (1 mL). Theresulting orange reaction solution was stirred at rt under nitrogenovernight. More Pd(dba)₂ (5.6 mg, 0.0097 mmol, 0.1 eq) and DPPB (4.1 mg,0.0097 mmol, 0.1 eq) were added. The resulting reaction mixture wasstirred at rt overnight. Then saturated aq. NaHCO₃ was added. Theresulting mixture was extracted with EtOAc (30 mL). The organic phasewas washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by preparative reversephase HPLC on a Waters Autopurification system using a Sunfire Prep C18OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; injection volume: 3.0 mL(CH₃CN); gradient: 20→100% B in A over 10 min; mass-directed fractioncollection]. Fractions containing the desired product were collected andfreeze-dried to yield the desired product S12-7-5-A (13.6 mg, 14%, MS(ESI) m/z 1013.51 (M+H)) along with di-deallylation product S12-7-3-A(23.6 mg) and starting material (61.7 mg).

Compounds S12-8-1-A and S12-8-1-B were prepared from the correspondingcompounds S12-7-3-A and S12-7-3-B separately using general procedure C.

S12-8-1-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.74 (d, J=6.9Hz, 1H), 3.88 (s, 1H), 3.73-3.67 (m, 1H), 3.38-3.30 (m, 2H), 3.16-3.07(m, 2H), 2.99 (s, 3H), 2.94-2.87 (m, 2H), 2.66 (d, J=13.3 Hz, 1H),2.56-2.47 (m, 1H), 2.28-2.22 (m, 2H), 2.12-2.04 (m, 1H), 1.60-1.50 (m,1H); MS (ESI) m/z 581.24 (M+H).

S12-8-1-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=7.3Hz, 1H), 3.88 (s, 1H), 3.73-3.65 (m, 1H), 3.36-3.30 (m, 2H), 3.14-3.06(m, 2H), 2.97 (s, 3H), 3.01-2.90 (m, 2H), 2.64 (d, J=11.9 Hz, 1H),2.56-2.47 (m, 1H), 2.28 (t, J=14.8 Hz, 1H), 2.22-2.18 (m, 1H), 2.14-2.05(m, 1H), 1.61-1.52 (m, 1H); MS (ESI) m/z 581.29 (M+H).

Compound S12-8-2-A was prepared from the corresponding compoundS12-7-5-A using general procedures D-1 (with formaldehyde), B and C.S12-8-2-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.76 (d, J=6.9Hz, 1H), 3.81 (s, 1H), 3.73-3.68 (m, 1H), 3.39-3.30 (m, 2H), 3.15-3.07(m, 2H), 3.00 (s, 3H), 2.96-2.92 (m, 2H), 2.92 (s, 3H), 2.85-2.79 (m,1H), 2.56-2.48 (m, 1H), 2.30-2.19 (m, 2H), 2.14-2.05 (m, 1H), 1.60-1.50(m, 1H); MS (ESI) m/z 595.27 (M+H).

Compounds S12-8-3-A and S12-8-3-B were prepared from the correspondingcompounds S12-7-3-A and S12-7-3-B separately using general procedures D1(with acetaldehyde) and C.

S12-8-3-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=6.9Hz, 1H), 3.87 (s, 1H), 3.73-3.67 (m, 1H), 3.48-3.32 (m, 4H), 3.16-3.06(m, 2H), 3.00 (s, 3H), 2.96-2.89 (m, 2H), 2.85 (d, J=12.4 Hz, 1H),2.56-2.47 (m, 1H), 2.28-2.21 (m, 2H), 2.13-2.04 (m, 1H), 1.59-1.49 (m,1H), 1.36 (t, J=7.3 Hz, 3H); MS (ESI) m/z 609.27 (M+H).

S12-8-3-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=6.9Hz, 1H), 3.86 (s, 1H), 3.70-3.64 (m, 1H), 3.44-3.30 (m, 4H), 3.13-3.05(m, 2H), 3.00 (s, 3H), 3.00-2.94 (m, 2H), 2.82 (d, J=12.8 Hz, 1H),2.54-2.47 (m, 1H), 2.27 (t, J=14.6 Hz, 1H), 2.21-2.16 (m, 1H), 2.12-2.06(m, 1H), 1.60-1.50 (m, 1H), 1.36 (t, J=7.3 Hz, 3H); MS (ESI) m/z 609.29(M+H).

Compound S12-8-4-A was prepared from compound S12-7-3-A using generalprocedures D-1 (with (tert-butyldimethylsilyloxy)acetaldehyde) and C.S12-8-4-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.75 (d, J=6.9Hz, 1H), 4.00 (s, 1H), 3.90-3.82 (m, 2H), 3.72-3.66 (m, 1H), 3.49-3.41(m, 2H), 3.38-3.32 (m, 2H), 3.14-3.06 (m, 2H), 2.99 (s, 3H), 2.96-2.86(m, 3H), 2.56-2.47 (m, 1H), 2.29-2.20 (m, 2H), 2.13-2.04 (m, 1H),1.60-1.51 (m, 1H); MS (ESI) m/z 625.30 (M+H).

Compound S12-8-5-A was prepared from compound S12-7-3-A using generalprocedures D-1 (twice, with acetaldehyde followed by formaldehyde) andC.

S12-8-5-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers)δ 4.75 (d, J=7.3 Hz, 1H), 4.23 (s, 0.5H), 4.14 (s, 0.5H), 3.74-3.68 (m,1H), 3.53-3.44 (m, 1H), 3.39-3.32 (m, 3H), 3.16-3.09 (m, 2H), 3.02-2.90(m, 9H), 2.56-2.47 (m, 1H), 2.30-2.20 (m, 2H), 2.13-2.04 (m, 1H),1.68-1.56 (m, 1H), 1.43-1.36 (m, 3H); MS (ESI) m/z 623.32 (M+H).

Compounds S12-8-6A and S12-8-6B were prepared from the correspondingcompounds S12-7-4-A and S12-7-4-B separately using general procedure C.

S12-8-6-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.83 (d, J=6.9Hz, 1H), 3.88 (s, 1H), 3.45-3.36 (m, 3H), 3.07 (dd, J=4.1, 15.1 Hz, 1H),2.97 (dd, J=11.2, 12.8 Hz, 1H), 2.90-2.75 (m, 2H), 2.66-2.64 (m, 1H),2.44-2.35 (m, 1H), 2.32-2.21 (m, 2H), 2.15-2.07 (m, 1H), 1.62-1.52 (m,1H); MS (ESI) m/z 567.28 (M+H).

S12-8-6-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 4.81 (d, J=6.9Hz, 1H), 3.89 (s, 1H), 3.44-3.37 (m, 3H), 3.05 (dd, J=3.7, 15.1 Hz, 1H),2.98-2.91 (m, 2H), 2.80-2.72 (m, 1H), 2.65 (d, J=12.8 Hz, 1H), 2.42-2.33(m, 1H), 2.28-2.18 (m, 2H), 2.14-2.06 (m, 1H), 1.60-1.51 (m, 1H); MS(ESI) m/z 567.26 (M+H).

Compound S12-8-7-A was prepared from compound S12-7-4-A using generalprocedures D-1 (with acetaldehyde) and C. S12-8-7-A: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt) δ 4.81 (d, J=6.9 Hz, 1H), 3.86 (s, 1H),3.45-3.33 (m, 5H), 3.04 (dd, J=4.1, 15.1 Hz, 1H), 2.96 (dd, J=11.0, 12.4Hz, 1H), 2.90-2.74 (m, 3H), 2.42-2.33 (m, 1H), 2.29-2.19 (m, 2H),2.13-2.05 (m, 1H), 1.58-1.48 (m, 1H), 1.35 (t, J=7.3 Hz, 3H); MS (ESI)m/z 595.31 (M+H).

Compound S12-8-8-A was prepared from compound S12-7-4-A using generalprocedures D-1 (twice, with acetaldehyde followed by formaldehyde) andC. S12-8-8-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1conformers) δ 4.82 (d, J=7.3 Hz, 1H), 4.22 (s, 0.5H), 4.13 (s, 0.5H),3.53-3.35 (m, 5H), 3.07 (dd, J=4.1, 15.6 Hz, 1H), 3.02-2.93 (m, 6H),2.82-2.77 (m, 1H), 2.43-2.34 (m, 1H), 2.31-2.20 (m, 2H), 2.14-2.06 (m,1H), 1.68-1.56 (m, 1H), 1.42-1.34 (m, 3H); MS (ESI) m/z 609.33 (M+H).

The following compounds were prepared according to Scheme 13.

To a solution of compound S13-1 (100 mg, 0.205 mmol, 1.5 eq, preparedaccording to literature procedures including J. Med. Chem., 2011, 54,3704) and enone S2-7-3 (72 mg, 0.136 mmol, 1.0 eq) in THF (3 mL) wasadded LDA solution in THF (˜1.2M, 2.73 mL, 0.34 mmol, 2.5 eq) dropwisevia a syringe at −78° C. The resulting red orange solution was allowedto gradually warm up to −10° C. A saturated aqueous NH₄Cl (20 mL)solution was added to the reaction. The reaction mixture was extractedwith DCM (3×15 mL). The combined organic phase was dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;injection volume: 3.0 mL (CH₃CN); gradient: 85→100% B in A over 8 min;mass-directed fraction collection]. Fractions containing the desiredproduct were collected and concentrated to yield the desired productS13-2 (52.8 mg, 42%, yellow solid): ¹H NMR (400 MHz, CDCl₃) δ 15.94 (s,1H), 8.24 (br s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.69 (dd, J=1.8, 8.5 Hz,1H), 7.50-7.48 (m, 2H), 7.39-7.32 (m, 3H), 5.37, 5.33 (ABq, J=12.2 Hz,2H), 3.96 (d, J=10.4 Hz, 1H), 3.85 (s, 3H), 3.77-3.71 (m, 4H), 3.46 (dd,J=4.3, 15.3 Hz, 1H), 3.08-3.02 (m, 3H), 2.65-2.49 (m, 5H), 2.24 (d,J=14.0 Hz, 1H), 1.58 (s, 9H), 0.81 (s, 9H), 0.25 (s, 3H), 0.12 (s, 3H);MS (ESI) m/z 917.36, 919.34 (M+H).

A solution of phenyllithium in di-n-butyl ether (1.03M, 112 μL, 0.115mmol, 2.0 eq) was added dropwise to a solution of compound S13-2 (52.8mg, 0.058 mmol, 1.0 eq) in tetrahydrofuran (2 mL) at −78° C., forming ared solution. After 5 min, a solution of n-butyllithium in hexanes(1.84M, 47 μL, 0.086 mmol, 1.5 eq) was added dropwise at −78° C.followed 1 min later by N,N-dimethylformamide (22 μL, 0.288 mmol, 5.0eq). The deep red reaction mixture was stirred at −78° C. for 1 h.Saturated aqueous ammonium chloride solution (10 mL) was added dropwiseat −78° C., followed by aqueous potassium phosphate buffer solution (pH7.0, 0.2M, 10 mL). The reaction mixture was allowed to warm up to rt,then was extracted with dichloromethane (3×15 mL). The organic extractswere combined and the combined solution was dried over anhydrous sodiumsulfate. The dried solution was filtered and the filtrate wasconcentrated. The residue was purified by preparative reverse phase HPLCon a Waters Autopurification system using a Sunfire Prep C18 OBD column[5 m, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H;Solvent B: CH₃CN with 0.1% HCO₂H; gradient: 90→95% B over 10 min, then100% B for 5 min; mass-directed fraction collection]. Fractions with thedesired MW were collected and concentrated to afford the desired productS13-3 (28.3 mg, 57%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 15.92(br s, 1H), 10.17 (s, 1H), 8.59 (br s, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.10(dd, J=4.3, 8.5 Hz, 1H), 7.51-7.49 (m, 2H), 7.39-7.33 (m, 3H), 5.38,5.34 (ABq, J=12.2 Hz, 2H), 3.96 (d, J=10.4 Hz, 1H), 3.89 (s, 3H),3.79-3.71 (m, 4H), 3.52 (dd, J=4.3, 15.3 Hz, 1H), 3.10-3.02 (m, 3H),2.67-2.51 (m, 5H), 2.25 (d, J=14.8 Hz, 1H), 1.59 (s, 9H), 0.81 (s, 9H),0.24 (s, 3H), 0.13 (s, 3H); MS (ESI) m/z 867.44 (M+H).

General Procedure F for reductive amination. Azetidine (3.2 μL, 0.048mmol, 3.0 eq), acetic acid (3 μL, 0.048 mmol, 3.0 eq) and sodiumtriacetoxyborohydride (6.8 mg, 0.032 mmol, 2.0 eq) were added insequence to a solution of aldehyde S13-3 (14 mg, 0.016 mmol, 1.0 eq) in1,2-dichloroethane (1 mL) at rt. After stirring for 1 h, the reactionmixture was poured into saturated aqueous sodium bicarbonate solution.The product was extracted into dichloromethane (3×15 mL). The combinedorganic extracts were dried over anhydrous sodium sulfate. The driedsolution was filtered and the filtrate was concentrated to yieldintermediate S13-4-1, which was deprotected using general procedure C togive compound S13-5-1: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ8.53 (br s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.75 (dd, J=1.4, 8.7 Hz, 1H),4.56 (s, 2H), 4.29-4.22 (m, 2H), 4.14-4.08 (m, 2H), 4.08 (s, 1H),4.07-3.98 (m, 4H), 3.80 (s, 3H), 3.62-3.57 (m, 4H), 3.14-3.10 (m, 1H),3.05-2.99 (m, 1H), 2.85-2.75 (m, 1H), 2.62-2.54 (m, 1H), 2.52-2.45 (m,1H), 2.41 (t, J=13.7 Hz, 1H), 2.28-2.24 (m, 1H), 1.73-1.63 (m, 1H); MS(ESI) m/z 606.38 (M+H).

Compound S13-5-2 was prepared from aldehyde S13-3 using generalprocedures F (with cyclopropylamine) and C. S13-5-2: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt) δ 8.57 (d, J=1.4 Hz, 1H), 8.11 (d, J=8.2 Hz,1H), 7.81 (dd, J=1.8, 8.7 Hz, 1H), 4.51 (s, 2H), 4.11 (s, 1H), 4.07-3.95(m, 4H), 3.81 (s, 3H), 3.62-3.57 (m, 4H), 3.41 (dd, J=4.6, 15.1 Hz, 1H),3.12 (d, J=12.8 Hz, 1H), 3.06-2.98 (m, 1H), 2.86-2.81 (m, 1H), 2.39 (t,J=13.7 Hz, 1H), 2.28-2.26 (m, 1H), 1.72-1.62 (m, 1H), 0.95-0.90 (m, 4H);MS (ESI) m/z 606.34 (M+H).

The following compounds were prepared according to Scheme 14.

To a solution of S4-5 (3.06 g, 9.53 mmol, 1 eq) in methylene chloride(19 mL) at −78° C. was added BBr₃ (9.53 mL, 1.0M/CH₂Cl₂, 9.53 mmol, 1eq) drop wise. The reaction mixture was stirred at −78° C. for 15 minand at 0° C. for 30 min. Saturated aqueous NaHCO₃ was added. The mixturewas stirred at rt for 10 min and extracted with EtOAc (2 times). Theorganic extracts were combined, washed with brine, dried over sodiumsulfate, and concentrated under reduced pressure to yield the desiredproduct S14-1 as a white solid, which was used in the next reactionwithout further purification: ¹H NMR (400 MHz, CDCl₃) δ 11.13 (s, 1H),7.42-7.48 (m, 2H), 7.29-7.33 (m, 1H), 7.15-7.20 (m, 2H), 7.08 (s, 1H),6.97 (s, 1H), 2.66 (s, 3H); MS (ESI) m/z 305.0 (M−H).

To a solution of S14-1 (9.53 mmol, 1 eq) in acetone (19 mL) was addedK₂CO₃ (2.63 g, 15.00 mmol, 1.5 eq) and BnBr (1.19 mL, 10.00 mmol, 1.05eq). The mixture was stirred at rt overnight and filtered through aCelite pad. The Celite pad was washed with EtOAc. The combined filtratewas concentrated under reduced pressure. Flash chromatography on silicagel with 0%-5% EtOAc/hexanes yielded the desired product S14-2 as awhite solid (3.61 g, 96% over 2 steps): ¹H NMR (400 MHz, CDCl₃) δ7.20-7.45 (m, 8H), 7.03-7.09 (m, 4H), 5.13 (s, 2H), 2.43 (s, 3H) MS(ESI) m/z 419.1 (M+Na).

To a pressure vial was charged with compound S14-2 (852 mg, 2.14 mmol, 1eq), N-Boc-2-pyrroleboronic acid (543 mg, 2.57 mmol, 1.2 eq),dichloro[1,1′-bis(diphenylphosphino)ferrrocene] palladium(II)dichloromethane adduct (88 mg, 0.11 mmol, 0.05 eq), and sodium carbonate(1.14 g, 10.7 mmol, 5 eq). The vial was briefly evacuated and filledwith N₂. Toluene (5 mL), 1,4-dioxane (5 mL), and H₂O (1 mL) were added.The reaction mixture was heated with a 90° C. oil bath for 2 h, cooledto rt, diluted with EtOAc, washed with aqueous phosphate buffer (pH=7)and brine, dried over Na₂SO₄, and concentrated. Purification of theresidue by Biotage flash chromatography gave compound S14-3 as acolorless oil (621 mg, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.48 (m,9H), 7.12 (d, J=7.8 Hz, 2H), 6.89 (d, J=7.8 Hz, 2H), 6.20-6.26 (m, 2H),5.15 (s, 2H), 2.48 (s, 3H), 1.41 (s, 9H); MS (ESI) m/z 484.4 (M+H).

Compound S14-3 (621 mg, 1.28 mmol, 1 eq) was dissolved in methanol. Pd—C(10% w/w, 186 mg) was added. The reaction flask was briefly evacuatedand re-filled with hydrogen. The reaction mixture was stirred under 1atm H₂ at rt for 2 h and filtered through a Celite pad. The Celite padwas washed with methanol. The filtrate was concentrated to give theintermediate as a white foam.

The above intermediate was dissolved in acetone (12 mL). K₂CO₃ (350 mg,2.54 mmol, 2 eq) and BnBr (0.16 mL, 1.33 mmol, 1.04 eq) were added.After stirring for an overnight at rt, the reaction mixture was filteredthrough a Celite pad. The Celite pad was washed with three portions ofEtOAc. The combined filtrate was concentrated. Purification of theresidue by Biotage flash chromatography gave compound S14-4 as colorlessoil (504 mg, 81%): ¹H NMR (400 MHz, CDCl₃, rotamer) δ 7.22-7.48 (m, 8H),7.05-7.15 (m, 2H), 6.63-6.70 (m, 2H), 5.13 (s, 2H), 4.90 and 4.76 (br s,1H), 3.50-3.65 (m, 2H), 2.43 (s, 3H), 2.25-2.28 (m, 1H), 1.72-1.90 (m,3H), 1.48 (s, 3H), 1.26 (s, 6H); MS (ESI) m/z 488.4 (M+H).

To a solution of compound S14-4 (556 mg, 1.14 mmol, 1 eq) in 5 mL ofCH₃CN was added NCS (160 mg, 1.20 mmol, 1.05 eq) in one portion. Thereaction mixture was heated with a 60° C. oil bath for 18 h, cooled tort, and evaporated to dryness. The residue was suspended in 200 mLCH₂Cl₂, washed with aqueous NaOH (1N), H₂O and brine, dried over Na₂SO₄,and concentrated. Purification of the residue by Biotage flashchromatography gave compound S14-4-a as a white solid (447 mg, 75%): ¹HNMR (400 MHz, CDCl₃, mixtures of rotamers) δ 7.22-7.48 (m, 8H),7.05-7.15 (m, 2H), 6.63-6.70 (m, 1H), 5.06-5.26 (m, 3H), 3.47-3.58 (m,2H), 2.46 (s, 3H), 2.25-2.28 (m, 1H), 1.55-1.88 (m, 3H), 1.48 (s, 3H),1.26 (s, 6H); MS (ESI) m/z 522.4 (M+H).

Compound S14-4-a (447 mg, 0.86 mmol) was suspended in HCl/1,4-dioxane(4.0M, 9 mL). After stirring at rt for 1 h, the volatiles wereevaporated. The residue was suspended in EtOAc, washed with saturatedaqueous NaHCO₃ and brine, dried over Na₂SO₄, and concentrated.Purification of the residue by Biotage flash chromatography gavecompound S14-5-1 as an off-white solid (338 mg, 93%): ¹H NMR (400 MHz,CDCl₃) δ 7.48 (dd, J=1.8, 7.8 Hz, 2H), 7.34-7.42 (m, 6H), 7.26 (t, J=7.8Hz, 1H), 7.14 (d, J=7.8 Hz, 2H), 5.20 (s, 2H), 4.57 (t, J=7.4 Hz, 1H),3.04-3.18 (m, 2H), 2.52 (s, 3H), 2.34-2.45 (m, 1H), 2.06 (br s, 1H),1.78-1.85 (m, 2H), 1.44-1.54 (m, 1H); MS (ESI) m/z 422.4 (M+H).

To a solution of compound S14-5-1 (100 mg, 0.237 mmol, 1 eq) in DCM (3mL) was added benzaldehyde (36 μL, 0.356 mmol, 1.5 eq), acetic acid (27μL, 0.474 mmol, 2.0 eq) and sodium triacetoxyborohydride (100 mg, 0.474mmol, 2.0 eq) in sequence. The resulting reaction mixture was stirred atrt for 1.5 h, and quenched with saturated aqueous sodium bicarbonatesolution. The product was extracted into dichloromethane (3×15 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate. Thedried solution was filtered and the filtrate was concentrated. Flashchromatography on silica gel using 1%→15% EtOAc/hexanes yielded thedesired product S14-5-2 (60 mg, 49%) as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 7.53 (s, 1H), 7.44-7.42 (m, 2H), 7.38-7.28 (m, 9H), 7.26-7.22(m, 2H), 7.10-7.08 (m, 2H), 5.19, 5.14 (ABq, J=11.6 Hz, 2H), 3.97 (t,J=7.9 Hz, 1H), 3.85 (d, J=13.4 Hz, 1H), 3.20 (d, J=13.4 Hz, 1H),3.18-3.13 (m, 1H), 2.49 (s, 3H), 2.46-2.36 (m, 1H), 2.31 (q, J=8.5 Hz,1H), 1.86-1.78 (m, 2H), 1.56-1.45 (m, 1H); MS (ESI) m/z 512.27 (M+H).

Compound S14-6-2 was prepared in 89% yield from S14-5-2 andN-methylallyl enone S1-9-5 using general procedure A. S14-6-2: ¹H NMR(400 MHz, CDCl₃, ˜1:1 diastereomers) δ 16.08 (s, 0.5H), 16.07 (s, 0.5H),7.57 (d, J=7.3 Hz, 1H), 7.52-7.44 (m, 4H), 7.41-7.21 (m, 11H), 5.91-5.82(m, 1H), 5.38 (s, 2H), 5.30-5.17 (m, 4H), 4.09 (d, J=10.4 Hz, 1H), 3.96(q, J=8.5 Hz, 1H), 3.80 (t, J=14.0 Hz, 1H), 3.48-3.40 (m, 2H), 3.33-3.14(m, 3H), 3.07-2.96 (m, 1H), 2.65-2.29 (m, 7H), 2.20 (d, J=14.0 Hz, 1H),1.85-1.77 (m, 3H), 1.53-1.43 (m, 1H), 0.87 (s, 4.5H), 0.86 (s, 4.5H),0.30 (s, 3H), 0.18 (s, 1.5H), 0.17 (s, 1.5H); MS (ESI) m/z 926.53 (M+H).

Compound S14-6-2-a was prepared in 70% yield from compound S14-6-2 usinggeneral procedure B. S14-6-2-a: ¹H NMR (400 MHz, CDCl₃, ˜1:1diastereomers) δ 16.57 (s, 1H), 7.55 (d, J=6.7 Hz, 1H), 7.51-7.47 (m,4H), 7.38-7.22 (m, 11H), 5.40, 5.36 (ABq, J=12.2 Hz, 2H), 5.29-5.13 (m,2H), 7.92 (dt, J=1.8, 7.9 Hz, 1H), 3.81 (d, J=13.4 Hz, 0.5H), 3.76 (d,J=13.4 Hz, 0.5H), 3.66 (d, J=1.8 Hz, 1H), 3.28-3.12 (m, 3H), 2.86-2.76(m, 1H), 2.72 (d, J=12.2 Hz, 1H), 2.60 (s, 3H), 2.43-2.19 (m, 2H),2.10-2.03 (m, 1H), 1.82-1.76 (m, 2H), 1.62-1.43 (m, 3H), 0.74 (s, 9H),0.21 (s, 3H), 0.11 (s, 3H); MS (ESI) m/z 886.51 (M+H).

Compound S14-8-1 was prepared from compound S14-6-2-a using generalprocedure E. S14-8-1: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1diastereomers) δ 7.42-7.40 (m, 2H), 7.35-7.30 (m, 3H), 7.224 (s, 0.5H),7.222 (s, 0.5H), 5.19-5.11 (m, 1H), 4.49, 4.36 (ABq, J=13.3 Hz, 1H),4.48, 4.35 (ABq, J=13.3 Hz, 1H), 3.85 (s, 0.5H), 3.84 (s, 0.5H),3.82-3.73 (m, 1H), 3.57-3.50 (m, 1H), 3.36-3.27 (m, 1H), 3.03-3.29 (m,1H), 3.94 (s, 1.5H), 3.92 (s, 1.5H), 2.85 (t, J=13.7 Hz, 1H), 2.71-2.63(m, 1H), 2.35-2.21 (m, 4H), 2.13-2.01 (m, 1H), 1.61-1.50 (m, 1H); MS(ESI) m/z 594.27 (M+H).

Compound S14-8-2 was prepared from compound S14-6-2-a using generalprocedures D-1 (with acetaldehyde) and E. S14-8-2: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt, ˜1:1 diastereomers) δ 7.42-7.40 (m, 2H),7.36-7.31 (m, 3H), 7.23 (s, 0.5H), 7.22 (s, 0.5H), 5.19-5.11 (m, 1H),4.50, 4.36 (ABq, J=12.2 Hz, 1H), 4.48, 4.35 (ABq, J=12.2 Hz, 1H), 4.25(s, 0.5H), 4.17 (s, 0.5H), 3.82-3.74 (m, 1H), 3.58-3.46 (m, 2H),3.38-3.32 (m, 2H), 3.10-2.94 (m, 5H), 2.69-2.63 (m, 1H), 2.36-2.23 (m,4H), 2.12-2.03 (m, 1H), 1.71-1.59 (m, 1H), 1.46-1.37 (m, 3H); MS (ESI)m/z 622.33 (M+H).

Compound S14-6-1 was prepared in 24% yield from S14-5-1 and N-diallylenone S1-9-2 using general procedure A (with the exception that 2.6equivalents of LDA were used). S14-6-1 (˜1:1 diastereomers): MS (ESI)m/z 862.44 (M+H).

Compound S14-7 was prepared from compound S14-6-1 using generalprocedure D-1 (with acetaldehyde). MS (ESI) m/z 890.52 (M+H).

Compound S14-7-a was prepared in 80% yield over 2 steps from crudecompound S14-7 using general procedure B. S14-7-a: MS (ESI) m/z 810.43(M+H).

Compound S14-7-b was prepared from compound S14-7-a using the first stepof general procedure C followed by Boc protection. Thus, the crudedesilyllation product (MS (ESI) m/z 696.31 (M+H)) was dissolved in DCM(2 mL). Boc₂O (16 mg, 0.072 mmol, 3.0 eq) and DMAP (cat.) were added.The resulting reaction solution was stirred at rt overnight. Thereaction was concentrated to yield compound S14-7-b, which was useddirectly for the hydrogenation reaction below. S14-7-b: MS (ESI) m/z796.39 (M+H).

Compound S14-8-3 was prepared from compound S14-7-b using the secondstep of general procedure C followed by HCl/MeOH treatment. Thus thecrude hydrogenation product was dissolved in 1M HCl/MeOH (1 mL). Theresulting reaction solution was stirred at rt for 30 min andconcentrated. The residue was purified by preparative reverse phase HPLCon a Waters Autopurification system using a Phenomenex Polymerx 10μ RP-γ100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05NHCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05N HCl/water);gradient: 0→35% B in A over 20 min; mass-directed fraction collection].Fractions containing the desired product were collected and freeze-driedto yield compound S14-8-3-A (1.07 mg, early eluting product) andcompound S14-8-3-B (1.11 mg, later eluting product).

S14-8-3-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.22 (s, 1H),5.10-5.05 (m, 1H), 3.93-3.89 (m, 2H), 3.44-3.15 (m, 3H), 3.06-2.99 (m,1H), 2.68-2.62 (m, 2H), 2.44 (t, J=14.2 Hz, 1H), 2.36-2.23 (m, 4H),2.16-2.08 (m, 1H), 1.65-1.56 (m, 1H), 1.29 (t, J=7.3 Hz, 3H); MS (ESI)m/z 518.22 (M+H).

S14-8-3-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt) δ 7.22 (s, 1H),5.08-5.04 (m, 1H), 3.94-3.88 (m, 2H), 3.44-3.15 (m, 3H), 3.06-2.99 (m,1H), 2.70-2.64 (m, 2H), 2.43 (t, J=16.0 Hz, 1H), 2.36-2.25 (m, 4H),2.17-2.10 (m, 1H), 1.66-1.57 (m, 1H), 1.29 (t, J=7.3 Hz, 3H); MS (ESI)m/z 518.22 (M+H).

The following compounds were prepared according to Scheme 15.

To a solution of diisopropylamine (0.57 mL, 4.07 mmol, 1.5 eq) in THF (5mL) at −78° C. was added ^(n)BuLi (2.54 mL, 1.6M in hexane, 4.07 mmol,1.5 eq) dropwise. The reaction was stirred at 0° C. for 10 min andcooled to −78° C. A solution of compound S15-1 (1.49 g, 2.70 mmol, 1 eq,prepared according to literature procedures including WO2011123536) inTHF (5 mL) was added dropwise over 5 min. The reaction was stirred at−78° C. for 30 min. CuI powder (0.39 g, 2.05 mmol, 0.75 eq) was added.The reaction was stirred at −78° C. for 1 h. Allylbromide (0.48 mL, 5.36mmol, 2 eq) was added. The reaction was stirred from −78° C. to rtovernight and quenched with saturated aqueous ammonium chloride (100mL). The reaction mixture was extracted with methylene chloride (50mL×3). The combined methylene chloride extracts were dried over sodiumsulfate and concentrated. Flash chromatography on silica gel with 0-10%EtOAc/hexanes yielded compound S15-2 as a pale oil (1.32 g, 93%): ¹H NMR(400 MHz, CDCl₃) δ 7.30-7.40 (m, 7H), 7.19-7.28 (m, 1H), 6.99 (d, J=8.0Hz, 2H), 5.78-5.90 (m, 1H), 5.08 (d, J=21.0 Hz, 1H), 5.03 (d, J=10.4 Hz,1H), 4.95 (s, 2H), 3.33 (d, J=6.1 Hz, 2H), 2.37 (d, J=2.4 Hz, 3H), 1.37(s, 18H); MS (ESI) m/z 590.3 (M−H).

To a solution of compound S15-2 (1.32 g, 2.23 mmol, 1 eq) in acetone (10mL) was added water (0.57 mL), NMO (0.31 g, 2.65 mmol, 1.2 eq), and OsO₄(0.14 mL, 4% in water, 0.022 mmol, 0.01 eq). The resulting reactionmixture was stirred at 40° C. for 3 h and cooled to rt. Aqueous Na₂S₂O₃solution (20 mL, 2M) and water (20 mL) were added. The mixture wasextracted with EtOAc (40 mL×3). The combined EtOAc extracts were driedover sodium sulfate and concentrated. Flash chromatography on silica gelwith 0-80% EtOAc/hexanes yielded compound S15-3 as a white solid (1.27g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.40 (m, 7H), 7.20-7.27 (m, 1H),7.01 (d, J=7.3 Hz, 2H), 4.94 (s, 2H), 4.02-4.10 (m, 1H), 3.68 (dd,J=3.6, 11.6 Hz, 1H), 3.53 (dd, J=6.1, 10.0 Hz, 1H), 2.72-2.85 (m, 2H),2.38 (d, J=2.4 Hz, 3H), 1.40 (s, 18H); MS (ESI) m/z 626.2 (M+H).

To a solution of compound S15-3 (2.22 g, 3.55 mmol, 1 eq) and imidazole(0.36 g, 5.29 mmol, 1.5 eq) in methylene chloride (20 mL) at rt wasadded a solution of TBSCl (0.64 g, 4.25 mmol, 1.2 eq) in methylenechloride (5 mL) dropwise over 5 min. The reaction was stirred at rtovernight. Saturated aqueous sodium bicarbonate solution (50 mL) wasadded. The mixture was extracted with methylene chloride (50 mL×3). Thecombined methylene chloride extracts were dried over sodium sulfate andconcentrated. Flash chromatography on silica gel with 0-20%EtOAc/hexanes yielded compound S15-4 as a colorless oil (2.25 g, 86%):¹H NMR (400 MHz, CDCl₃) δ 7.30-7.40 (m, 7H), 7.22-7.28 (m, 1H), 7.02 (d,J=7.3 Hz, 2H), 4.96 (s, 2H), 3.93-4.01 (m, 1H), 3.54-3.64 (m, 2H),2.82-2.88 (m, 1H), 2.71-2.78 (m, 1H), 2.39 (d, J=2.4 Hz, 3H), 1.40 (s,9H), 1.39 (s, 9H), 0.92 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); MS (ESI)m/z 740.2 (M+H).

To a solution of compound S15-4 (2.25 g, 3.04 mmol, 1 eq) in methylenechloride (20 mL) was added Dess-Martin reagent (3.87 g, 9.12 mmol, 3 eq)at rt. After stirring for 5 min, methylene chloride (140 mL) containingwater (0.164 mL, 9.12 mmol, 3 eq) was added. The resulting reaction wasstirred at rt for 1 h and quenched with saturated aqueous sodiumbicarbonate (50 mL) and aqueous Na₂S₂O₃ solution (50 mL, 2M). Theorganic layer was separated. The aqueous layer was extracted withmethylene chloride (100 mL×3). The combined organic layers were driedover sodium sulfate and concentrated. Flash chromatography on silica gelwith 0-15% EtOAc/hexanes yielded compound S15-5 (2.11 g, 94%): ¹H NMR(400 MHz, CDCl₃) δ 7.28-7.40 (m, 7H), 7.20-7.25 (m, 1H), 6.99 (d, J=7.9Hz, 2H), 4.94 (s, 2H), 4.25 (s, 2H), 3.82 (d, J=1.6 Hz, 2H), 2.38 (d,J=1.5 Hz, 3H), 1.36 (s, 18H), 0.93 (s, 9H), 0.11 (s, 6H); MS (ESI) m/z736.2 (M−H).

To a solution of compound S15-5 (1.01 g, 1.37 mmol, 1 eq) indichloroethane (4 mL) was added acetic acid (0.47 mL, 8.22 mmol, 6 eq),propylamine (0.56 mL, 6.84 mmol, 5 eq), and Na(OAc)₃BH (1.45 g, 6.84mmol, 5 eq). The resulting reaction mixture was stirred at rt for 3days. Saturated aqueous sodium bicarbonate (15 mL) was added. Theresulting mixture was stirred at rt for 15 min, and extracted withmethylene chloride (30 mL, then 2×15 mL). The combined methylenechloride extracts were dried over sodium sulfate, filtered andconcentrated to yield compound S15-6-3 as a pale yellow oil: MS (ESI)m/z 781.43 (M+H).

To a solution of the above crude compound S15-6-3 (1.37 mmol, 1 eq) inDCM (10 mL) was added Boc₂O (329 mg, 1.51 mmol, 1.1 eq) and DMAP (17 mg,0.14 mmol, 0.1 eq). The resulting reaction solution was stirred at rtfor 1.5 h. More Boc₂O (60 mg, 0.271 mmol, 0.2 eq) was added. Theresulting reaction was stirred at rt for 1 h and stored in fridge overthe weekend. The reaction was concentrated. The residue was purified byflash chromatography on silica gel with 0-15% EtOAc/hexanes to yield amixture of products (835 mg), which were dissolved in MeCN (22.5 mL) ina polypropylene reaction vessel. A solution of HF in MeCN (1M in aqueousacetonitrile, prepared from 48% aqueous HF and acetonitrile, 2.84 mL,2.84 mmol) was added. The resulting reaction solution was stirred at rtfor 30 min and quenched with saturated sodium bicarbonate and brine. Theresulting mixture was extracted with EtOAc (50 mL×3). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated to yield compound S15-6-1: MS (ESI) m/z 879.51 (M−H).

To a solution of crude compound S15-6-1 (0.948 mmol, 1 eq) in THF (10mL) was added HOAc (108 μL, 1.90 mmol, 2 eq) followed by TBAF (1.0M inTHF, 1.04 mL, 1.04 mmol, 1.1 eq). The resulting reaction was stirred atrt for 4 h and more TBAF (0.9 eq) was added. The resulting reaction wasstirred at rt for 5 days and quenched with saturated aqueous sodiumbicarbonate. The mixture was extracted with EtOAc (60 mL). The organicphase was dried over sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel with 1-50%EtOAc/hexanes to yield compound S15-7-1 (631 mg, 60% over 3 steps) as awhite foamy solid: MS (ESI) m/z 765.37 (M−H).

To a solution of DMSO (0.88 mL, 12.34 mmol, 15 eq) in methylene chloride(10 mL) at −78° C. was added TFAA (1.15 mL, 8.23 mmol, 10 eq). Theresulting suspension was warmed up to −40° C. and then cooled back to−78° C. A solution of compound S15-7-1 (631 mg, 0.823 mmol, 1 eq) inmethylene chloride (3 mL) was added dropwise. The reaction was stirredat −78° C. for 3 h. Triethylamine (2.29 mL, 16.46 mmol, 20 eq) wasadded. The reaction was stirred at −78° C. for 10 min and warmed up tort over 2 h, quenched with saturated aqueous sodium bicarbonate. Theresulting mixture was extracted with DCM (30 mL, then 10 mL). Thecombined organic phase was dried over sodium sulfate, filtered andconcentrated to yield the crude aldehyde intermediate: MS (ESI) m/z765.31 (M+H).

The above aldehyde intermediate was dissolved in t-butanol (6 mL) andwater (6 mL). NaH₂PO₄H₂O (565 mg, 4.11 mmol, 5 eq) was added. Theresulting solution was cooled to 0° C., followed by the addition of2-methyl-2-butylene (435 μL, 4.11 mmol, 5 eq) and NaClO₂ (4.94 mL, 0.5Min t-butanol/water (2:1, v/v), 2.46 mmol, 3 eq). The reaction wasstirred at 0° C. for 30 min. Saturated aqueous ammonium chloride wasadded. The mixture was extracted with EtOAc (60 mL). The organic phasewas washed with brine, dried over sodium sulfate, filtered andconcentrated. Flash chromatography on silica gel with 10-80%EtOAc/hexanes yielded compound S15-8-1 as a yellow solid (640 mg, 100%over 2 steps): MS (ESI) m/z 779.33 (M−H).

Compound S15-9-1 was prepared in 20% yield from S15-8-1 and N-diallylenone S1-9-2 using general procedure A (except that 3.5 equivalents ofLDA were used). S15-9-1 (˜1:1 diastereomers): MS (ESI) m/z 1221.53(M+H).

Compound S15-9-1-a was prepared in 64% yield from compound S15-9-1 usinggeneral procedure B. S15-9-1-a (˜1:1 diastereomers): MS (ESI) m/z1141.44 (M+H).

Compound S15-10-1 was prepared from compound S15-9-1-a using generalprocedure E. S15-10-1: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1diastereomers) δ 4.37-4.32 (m, 1H), 3.88 (s, 1H), 3.70-3.63 (m, 1H),3.21-2.98 (m, 5H), 2.65 (d, J=12.8 Hz, 1H), 2.23-2.22 (m, 2H), 1.86-1.76(m, 2H), 1.66-1.54 (m, 1H), 1.073 (t, J=7.3 Hz, 1.5H), 1.069 (t, J=7.3Hz, 1.5H); MS (ESI) m/z 531.12 (M+H).

Compound S15-10-2 was prepared from compound S15-9-1-a using generalprocedures D-1 (with acetaldehyde) and E. S15-10-2: ¹H NMR (400 MHz,CD₃OD, hydrochloride salt, ˜1:1 diastereomers) δ 4.34 (dd, J=5.5, 14.6Hz, 1H), 3.86 (s, 1 H), 3.70-3.63 (m, 1H), 3.47-3.30 (m, 2H), 3.25-3.12(m, 3H), 3.06-2.98 (m, 2H), 2.84 (d, J=12.8 Hz, 1H), 2.31-2.21 (m, 2H),1.86-1.75 (m, 2H), 1.61-1.52 (m, 1H), 1.362 (t, J=7.3 Hz, 1.5H), 1.358(t, J=7.3 Hz, 1.5H), 1.072 (t, J=7.3 Hz, 1.5H), 1.068 (t, J=7.3 Hz,1.5H); MS (ESI) m/z 559.16 (M+H).

Compound S15-10-3 was prepared from compound S15-9-1-a using generalprocedure D-1 (twice, with acetaldehyde followed by formaldehyde) and E.S15-10-3: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1diastereomers) δ 4.35 (dd, J=6.4, 14.6 Hz, 1H), 4.22 (s, 0.5H), 4.13 (s,0.5H), 3.71-3.64 (m, 1H), 3.52-3.44 (m, 1H), 3.38-3.30 (m, 1H),3.23-3.12 (m, 3H), 3.07-2.93 (m, 6H), 2.32-2.21 (m, 2H), 1.86-1.75 (m,2H), 1.70-1.58 (m, 1H), 1.43-1.36 (m, 3H), 1.07 (t, J=7.3 Hz, 3H); MS(ESI) m/z 573.16 (M+H).

To a solution of compound S15-6-3 (0.686 mmol, crude, 1 eq) inacetonitrile (2 mL) was added potassium carbonate (190 mg, 1.37 mmol, 2eq) and allylbromide (74 μL, 0.823 mmol, 1.2 eq). The resulting reactionmixture was stirred at rt for 2 days. Brine (50 mL) was added. Themixture was extracted with EtOAc (40 mL). The organic phase was washedwith brine, dried over sodium sulfate, filtered and concentrated. Flashchromatography on silica gel with 0-10% EtOAc/hexanes yielded compoundS15-6-2 as a colorless oil (415 mg, 74% for two steps): ¹H NMR (400 MHz,CDCl₃) δ 7.34-7.26 (m, 7H), 7.21 (t, J=7.3 Hz, 1H), 6.99 (d, J=7.9 Hz,2H), 5.81-5.71 (m, 1H), 5.12 (d, J=17.1 Hz, 1H), 4.96 (d, J=9.2 Hz, 1H),4.86, 4.82 (ABq, J=10.4 Hz, 2H), 3.59 (dd, J=6.7, 10.4 Hz, 1H), 3.50(dd, J=3.7, 10.4 Hz, 1H), 3.30 (dd, J=6.1, 14.6 Hz, 1H), 3.17 (dd,J=6.1, 14.6 Hz, 1H), 3.10-3.04 (m, 1H), 2.80 (dd, J=9.2, 13.4 Hz, 1H),2.59-2.44 (m, 3H), 2.32 (d, J=1.8 Hz, 3 H), 1.39 (s, 9H), 1.38-1.33 (m,2H), 1.26 (s, 9H), 0.82 (s, 9H), 0.78 (t, J=7.3 Hz, 3H), −0.032 (s, 3H),−0.057 (s, 3H); MS (ESI) m/z 590.3 (M−H). MS (ESI) m/z 821.23 (M+H).

To a solution of compound S15-6-2 (415 mg, 0.505 mmol, 1 eq) inacetonitrile (24 mL) in a polypropylene reaction vessel was added HF(1.52 mL, 1M in aqueous acetonitrile, prepared from 48% aqueous HF andacetonitrile, 1.52 mmol, 3 eq). The reaction was stirred at rt for 2 hand quenched with saturated aqueous sodium bicarbonate (5 mL). Theresulting reaction mixture was evaporated, and the residue was extractedwith EtOAc (40 mL). The organic phase was washed with brine, dried oversodium sulfate, filtered and concentrated to yield compound S15-7-2 as awhite foamy solid (crude): ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.30 (m, 7H),7.24 (t, J=7.3 Hz, 1H), 6.99 (d, J=7.9 Hz, 2H), 5.84-5.74 (m, 1H), 5.28(d, J=17.1 Hz, 1H), 5.14 (d, J=10.4 Hz, 1H), 4.92, 4.88 (ABq, J=10.4 Hz,2H), 3.41-3.36 (m, 2H), 3.26-3.15 (m, 3H), 3.01 (dd, J=7.9, 14.0 Hz,1H), 2.71 (dt, J=12.8, 3.0 Hz, 1H), 2.64-2.54 (m, 2H), 2.50-2.43 (m,1H), 2.37 (d, J=1.8 Hz, 3H), 1.61-1.51 (m, 2H), 1.46 (s, 9H), 1.33 (s,9H), 0.92 (t, J=7.3 Hz, 3H); MS (ESI) m/z 707.18 (M+H).

To a solution of DMSO (0.54 mL, 7.58 mmol, 15 eq) in methylene chloride(5 mL) at −78° C. was added TFAA (0.71 mL, 5.05 mmol, 10 eq). Theresulting suspension was stirred at −78° C. for 20 min. A solution ofthe above crude compound S15-7-2 (0.505 mmol, 1 eq) in methylenechloride (5 mL) was added dropwise. The reaction was stirred at −78° C.for 3 h. Triethylamine (1.41 mL, 10.1 mmol, 20 eq) was added. Thereaction was stirred at −78° C. for 10 min and warmed up to rt over 2 h,quenched with saturated aqueous sodium bicarbonate. The resultingmixture was extracted with EtOAc (50 mL). The organic phase was driedover sodium sulfate, filtered and concentrated to yield the crudealdehyde intermediate: MS (ESI) m/z 705.15 (M+H).

The above aldehyde intermediate was dissolved in t-butanol (7.5 mL) andwater (7.5 mL). NaH₂PO₄H₂O (348 mg, 2.52 mmol, 5 eq) was added. Theresulting solution was cooled to 0° C., followed by the addition of2-methyl-2-butylene (267 μL, 2.52 mmol, 5 eq) and NaClO₂ (3.03 mL, 0.5Min t-butanol-water (2:1, v/v), 1.52 mmol, 3 eq). The reaction wasstirred at 0° C. for 1 h. Saturated aqueous ammonium chloride was added.The mixture was extracted with EtOAc (60 mL). The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentrated.Flash chromatography on silica gel with 10-100% EtOAc/hexanes yieldedcompound S15-8-2 as a colorless oil (76 mg, 21% over 3 steps): ¹H NMR(400 MHz, CDCl₃) δ 7.37-7.30 (m, 7H), 7.26-7.22 (m, 1H), 7.03-7.00 (m,2H), 5.84-5.74 (m, 1H), 5.22 (d, J=10.4 Hz, 1H), 5.18 (d, J=18.9 Hz,1H), 4.92 (s, 2H), 4.04 (t, J=6.7 Hz, 1H), 3.68 (dd, J=6.1, 14.6 Hz,1H), 3.35 (dd, J=5.5, 14.0 Hz, 1H), 3.21 (dd, J=7.3, 14.0 Hz, 1H), 2.81(dd, J=7.6, 15.3 Hz, 1H), 2.63 (t, J=6.7 Hz, 2H), 2.38 (s, 3H),1.60-1.49 (m, 2H), 1.45 (s, 9H), 1.33 (s, 9H), 0.90 (t, J=7.3 Hz, 3H);MS (ESI) m/z 721.18 (M+H).

Compound S15-9-2 was prepared in 44% yield from S15-8-2 andN-methylethyl enone S1-9-1 using general procedure A (except that 2.2equivalents of LDA were used) as a mixture of two diastereomers, whichwere separated by preparative reverse phase HPLC on a WatersAutopurification system using a Sunfire Prep C18 OBD column [5 μm, 19×50mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B:MeOH with 0.1% HCO₂H; gradient: 85→92% B over 15 min, then 100% B for 5min; mass-directed fraction collection]. Fractions with the desired MWwere collected and concentrated to afford the desired product S15-9-2-A(20.3 mg, 17%, early eluting product) and S15-9-2-B (19.7 mg, 17%, latereluting product).

S15-9-2-A: ¹H NMR (400 MHz, CDCl₃, ˜1:1 rotamers) δ 16.02 (br s, 1H),7.51-7.48 (m, 4H), 7.38-7.32 (m, 6H), 5.85-5.75 (m, 1H), 5.35 (s, 2H),5.25-5.17 (m, 2H), 5.04 (dd, J=3.0, 9.2 Hz, 2H), 4.72 (dd, J=2.4, 9.2Hz, 1H), 4.06-4.03 (m, 1H), 3.98 (dd, J=3.0, 10.4 Hz, 1H), 3.52-3.38 (m,2H), 3.28-3.24 (m, 2H), 3.05-2.98 (m, 1H), 2.84-2.80 (m, 2H), 2.66 (brs, 3H), 2.58-2.39 (m, 6H), 2.17 (d, J=14.6 Hz, 1H), 1.59-1.53 (m, 2H),1.46 (s, 4.5H), 1.45 (s, 4.5H), 1.28 (s, 4.5H), 1.27 (s, 4.5H),1.14-1.10 (m, 3H), 0.90-0.87 (m, 3H), 0.82 (s, 4.5H), 0.81 (s, 4.5H),0.27 (s, 1.5H), 0.26 (s, 1.5H), 0.14 (s, 1.5H), 0.13 (s, 1.5H); MS (ESI)m/z 1123.18 (M+H).

S15-9-2-B: ¹H NMR (400 MHz, CDCl₃) δ 15.89 (br s, 1H), 7.50-7.48 (m,2H), 7.44-7.42 (m, 2H), 7.39-7.30 (m, 6H), 5.89-5.79 (m, 1H), 5.35 (s,2H), 5.32 (d, J=10.4 Hz, 1H), 5.22 (d, J=17.1 Hz, 1H), 4.82, 4.77 (ABq,J=9.2 Hz, 2H), 4.14 (t, J=6.1 Hz, 1H), 3.97 (d, J=10.4 Hz, 1H), 3.61(dt, J=4.9, 15.9 Hz, 1H), 3.41 (dd, J=7.3, 13.4 Hz, 1H), 3.24 (dd,J=7.9, 15.9 Hz, 1H), 3.06-2.99 (m, 1H), 2.96-2.86 (m, 2H), 2.85-2.74 (m,2H), 2.69-2.63 (m, 1H), 2.60-2.56 (m, 1H), 2.51-2.43 (m, 2H), 2.39 (s,3H), 2.19 (d, J=14.0 Hz, 1H), 1.65-1.59 (m, 2H), 1.39 (s, 9H), 1.35 (s,9H), 1.17 (t, J=7.3 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H), 0.82 (s, 9H), 0.27(s, 3H), 0.13 (s, 3H); MS (ESI) m/z 1123.18 (M+H).

Single diastereomer S15-9-2-B (19.7 mg, 0.018 mmol, 1 eq) was dissolvedin dioxane (0.25 mL). HCl-dioxane (0.25 mL, 4N) was added dropwise. Theresulting reaction solution was stirred at rt for 3 h and quenched withsaturated sodium bicarbonate solution (˜3 mL). The resulting reactionmixture was extracted with EtOAc (30 mL). The organic phase was driedover sodium sulfate, filtered and concentrated to yield compoundS15-9-2-a-B (crude): MS (ESI) m/z 905.31 (M+H). Single diastereomerS15-9-2-A was similarly converted to the corresponding singlediastereomer S15-9-2-a-A: MS (ESI) m/z 905.25 (M+H).

Single diastereomers S15-10-3-A and S15-10-3-B were prepared from thecorresponding compounds S15-9-2-a-A and S15-9-2-a-B separately usinggeneral procedures B and C.

S15-10-3-A: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers)δ 4.35 (dd, J=6.9, 14.6 Hz, 1H), 4.22 (s, 0.5H), 4.13 (s, 0.5H), 3.69(dd, J=6.9, 15.6 Hz, 1H), 3.53-3.46 (m, 1H), 3.38-3.31 (m, 1H),3.23-3.14 (m, 3H), 3.07-2.94 (m, 6H), 2.31-2.21 (m, 2H), 1.86-1.76 (m,2H), 1.70-1.58 (m, 1H), 1.44-1.37 (m, 3H), 1.07 (t, J=7.3 Hz, 3H); MS(ESI) m/z 573.09 (M+H).

S15-10-3-B: ¹H NMR (400 MHz, CD₃OD, hydrochloride salt, ˜1:1 conformers)δ 4.35 (dd, J=6.4, 14.6 Hz, 1H), 4.22 (s, 0.5H), 4.13 (s, 0.5H), 3.67(dd, J=6.9, 16.0 Hz, 1H), 3.54-3.46 (m, 1H), 3.38-3.30 (m, 1H),3.23-3.12 (m, 3H), 3.07-2.93 (m, 6H), 2.32-2.21 (m, 2H), 1.86-1.76 (m,2H), 1.70-1.58 (m, 1H), 1.43-1.36 (m, 3H), 1.07 (t, J=7.3 Hz, 3H); MS(ESI) m/z 573.09 (M+H).

The following compounds were prepared according to Scheme 16.

9-Borabicyclo[3.3.1]nonane solution (0.5M in THF, 27.0 mL, 13.5 mmol)was added to a solution of compound S3-3 (2.56 g, 0.4.49 mmol) in THF(20 mL). After 1 h, the reaction mixture was cooled to 0° C. and NaOH(6N aqueous solution, 6.75 mL, 40.4 mmol) was carefully added followedby hydrogen peroxide (30% aqueous solution, 4.6 mL, 40.4 mmol). After 10min, the reaction mixture was diluted with EtOAc and was washed withwater (2×) and brine (1×). The organics were dried over Na₂SO₄, werefiltered, and were concentrated under reduced pressure to yield thecrude product S16-1: ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.32 (m, 7H),7.28-7.22 (m, 1H), 7.02-6.97 (m, 2H), 4.92 (ABq, J=27.5 Hz, 10.1 Hz,2H), 3.99-3.90 (m, 1H), 3.88-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.59-3.51(m, 1H), 2.41 (d, J=2.3 Hz, 3H), 1.74-1.62 (m, 2H), 1.42 (s, 9H); MS(ESI) m/z 587.93, 589.93 (M+H).

2-Iodoxybenzoic acid (stabilized, 45 wt %, 3.07 g, 4.93 mmol) was addedto a solution of compound S16-1 (2.64 g, 4.49 mmol) in DMSO (12 mL).After 3 h, the reaction mixture was diluted with EtOAc and was filteredthrough Celite (EtOAc wash). The filtrate was washed with NaHCO₃(saturated, aqueous solution, 3×) and brine (1×). The organics weredried over Na₂SO₄, were filtered, and were concentrated under reducedpressure. The material was dissolved in toluene (10 mL), and copper(II)sulfate (2.15 g, 13.5 mmol) and (R)-(+)-t-butylsulfinamide (1.09 g, 8.98mmol) were added. After stirring for 2 days, the reaction mixture wasdiluted with EtOAc and was washed with water (3×) and brine (2×). Theorganics were dried over Na₂SO₄, were filtered, and were concentratedunder reduced pressure. The material was purified by columnchromatography (50 g Biotage column, 5 to 40% EtOAc in Hexanesgradient). This gave 1.165 mg (38%, 3 steps) of the desired productS16-2 as a thick oil: ¹H NMR (400 MHz, CDCl₃) mixture of rotamers or E/Zisomers, δ 8.09-7.98 (m, 1H), 7.38-7.32 (m, 7H), 7.28-7.22 (m, 1H),7.04-6.97 (m, 2H), 5.04-4.89 (m, 2H), 4.10-4.00 (m, 1H), 3.87-3.74 (m,1H), 3.00-2.72 (m, 2H), 2.44-2.38 (m, 3H), 1.53 (s, 3H), 1.42 (s, 6H),1.15-1.07 (m, 9H); MS (ESI) m/z 688.98, 690.98 (M+H).

t-Butyllithium (1.7M solution, 1.98 mL, 3.37 mmol) was added dropwise toa −100° C. solution of compound S16-2 (1.165 g, 1.689 mmol) in THF (20mL). After 5 min, the reaction mixture was quenched with NH₄Cl(saturated, aqueous solution), was diluted with EtOAc and was washedwith water (1×) and brine (1×). The organics were dried over Na₂SO₄,were filtered, and were concentrated under reduced pressure. Thematerial was purified by column chromatography (50 g Biotage column, 30to 90% EtOAc in Hexanes gradient). This gave 505 mg (49%) of the desiredproduct S16-3 as a white solid (single diastereomer): ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.34 (m, 2H), 7.33-7.22 (m, 6H), 7.10-7.04 (m, 2H),4.93-4.76 (m, 3H), 3.42-3.34 (m, 1H), 2.37-2.27 (m, 4H), 2.10-1.90 (m,2H), 1.33 (s, 9H), 1.16 (s, 9H); MS (ESI) m/z 611.74 (M+H).

Compound S16-3 (158 mg, 0.258 mmol) was stirred in HCl (4M solution in1,4-dioxane, 0.5 mL) and MeOH (2.5 mL). After 4 h, the reaction mixturewas diluted with EtOAc and was washed with NaHCO₃ (saturated, aqueoussolution, 3×) and brine (1×). The organics were dried over Na₂SO₄, werefiltered, and were concentrated under reduced pressure to give compoundS16-4 (single enantiomer): MS (ESI) m/z 507.19 (M+H).

Crude S16-4 (0.258 mmol) was dissolved in CH₂Cl₂ (5 mL) and Na(OAc)₃BH(219 mg, 1.03 mmol) and formaldehyde (37% aqueous solution, 1 mL) wereadded. After 30 min, the reaction mixture was diluted with EtOAc. Themixture was washed with NaHCO₃ (saturated, aqueous solution, 3×) andbrine (1×), was dried over Na₂SO₄, was filtered, and was concentrated.The material was purified by column chromatography (25 g Biotage column,20 to 80% EtOAc in Hexanes gradient) to give 117 mg (85%, 2 steps) ofthe product S16-5-1 (single diastereomer): ¹H NMR (400 MHz, CDCl₃) δ7.44-7.20 (m, 8H), 7.08-7.02 (m, 2H), 4.98-4.76 (m, 2H), 4.22-4.10 (m,1H), 3.90-3.82 (m, 1H), 3.10-2.98 (m, 1H), 2.38-2.27 (m, 4H), 2.20 (s,6H), 1.70-1.56 (m, 1H), 1.30 (s, 9H); MS (ESI) m/z 535.32 (M+H).

Crude S16-4 (0.247 mmol) was dissolved in CH₃CN (2 mL) and triethylamine(0.103 mL, 0.741 mmol) and 1,4-dibromobutane (0.0292 mL, 0.247 mmol)were added. The reaction mixture was heated to 130° C. for 15 min in amicrowave reactor. Additional 1,4-dibromobutane (0.050 mL, 0.42 mmol)was added, and the mixture was again heated to 130° C. for 15 min bymicrowave reactor. The reaction mixture was diluted with EtOAc, waswashed with NaHCO₃ (saturated, aqueous solution, 2×) and brine (1×), wasdried over Na₂SO₄, was filtered, and was concentrated. The material waspurified by column chromatography (10 g Biotage column, 20 to 60% EtOAcin Hexanes gradient) to give 41.2 mg (30%, 2 steps) of the productS16-5-2 (single enantiomer): ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.20 (m,8H), 7.08-7.01 (m, 2H), 5.00 and 4.79 (ABq, J=10.6 Hz, 2H), 4.22-4.10(m, 1H), 3.84-3.80 (m, 1H), 3.20-3.08 (m, 1H), 2.68-2.58 (m, 2H),2.42-2.30 (m, 6H), 1.76-1.55 (m, 5H), 1.30 (s, 9H); MS (ESI) m/z 561.23(M+H).

Lithium diisopropylamide was prepared from diisopropylamine (0.0382 mL,0.270 mmol) and n-BuLi (1.6M solution, 0.169 mL, 0.270 mmol) in THF (3mL) at −40° C. The reaction mixture was cooled to −78° C., and TMEDA(0.125 mL, 0.832 mmol) was added. A solution of compound S16-5-1 (117mg, 0.219 mmol) in THF (1 mL) was then added dropwise, resulting in anorange-red solution. The reaction mixture was stirred at −78° C. for 30min. A solution of enone S1-9-2 (111 mg, 0.208 mmol) in THF (1 mL) wasadded dropwise, followed by LHMDS (1.0M solution, 0.25 mL, 0.25 mmol).The reaction mixture was allowed to warm to −10° C. over 1 h. Thereaction was quenched by the addition of ammonium chloride (saturated,aqueous solution) and was diluted with EtOAc. The mixture was washedwith water (3×) and brine (1×), was dried over Na₂SO₄, was filtered, andwas concentrated under reduced pressure. The material was purified bycolumn chromatography (25 g Biotage column, 15 to 50% EtOAc in Hexanesgradient). This gave 116 mg of S16-6-1 (57%, single diastereomer): ¹HNMR (400 MHz, CDCl₃) δ 15.9 (s, 1H), 7.44-7.36 (m, 2H), 7.36-7.12 (m,8H), 5.87-5.65 (m, 2H), 5.26 (s, 2H), 5.20-5.00 (m, 4H), 4.96-4.84 (m,1H), 4.66-4.48 (m, 1H), 4.12-3.95 (m, 2H), 3.82-3.72 (m, 1H), 3.28-3.18(m, 2H), 3.17-3.00 (m, 3H), 2.95-2.80 (m, 2H), 2.51 (t, J=14.7 Hz, 1H),2.44-2.16 (m, 3H), 2.10 (s, 6H), 2.25-1.96 (m, 1H), 1.58-1.44 (m, 1H),1.33 (s, 2.7H), 1.07 (s, 5.3H), 0.68 (s, 9H), 0.15 (s, 3H), 0.00 (s,3H); MS (ESI) m/z 975.39 (M+H).

Compound S16-6-1 (42.2 mg, 0.0433 mmol), 1,3-dimethylbarbituric acid(27.0 mg, 0.173 mmol), and Pd(Ph₃P)₄ (5.0 mg, 0.0043 mmol) weredissolved in CH₂Cl₂ (2 mL), and the reaction mixture was evacuated andbackfilled with nitrogen (3×). After 6 h, the reaction mixture wasdiluted with EtOAc, was washed with NaHCO₃ (saturated, aqueous, 3×) andpH 7 phosphate buffer (1×), was dried over Na₂SO₄, was filtered, and wasconcentrated under reduced pressure. The material was purified by columnchromatography (10 g Biotage column, 50 to 100% EtOAc in Hexanesgradient). This gave 30.9 mg of S16-6-2 (80%, single diastereomer): MS(ESI) m/z 895.38 (M+H).

Compound S16-6-2 (30.9 mg, 0.0345 mmol) and acetic acid (0.0039 mL,0.069 mmol) were dissolved in MeOH (1 mL), and the reaction mixture wascooled to 0° C. Na(OAc)₃BH (14.6 mg, 0.069 mmol) and acetaldehyde (50 wt% solution in EtOH, 0.0026 mL, 0.0518 mmol) were added. After 10 min,˜90% conversion was observed by LC/MS. Additional Na(OAc)₃BH (14.6 mg,0.069 mmol) and acetaldehyde (50 wt % solution in EtOH, 0.0026 mL,0.0518 mmol) were added. After 5 min, the reaction mixture was quenchedwith NaHCO₃ (saturated, aqueous) and was diluted with EtOAc. The mixturewas washed with NaHCO₃ (saturated, aqueous, 2×) and pH 7 phosphatebuffer (1×), was dried over Na₂SO₄, was filtered, and was concentratedunder reduced pressure. This gave 28.5 mg (90%) of crude S16-6-4-1,which was used without further purification: MS (ESI) m/z 923.36 (M+H).

Formaldehyde (37% aqueous solution, 0.5 mL) was added to a mixture ofcompound S16-6-4-1 (14.3 mg, 0.0155 mmol) and Na(OAc)₃BH (9.8 mg, 0.046mmol) in CH₂Cl₂ (1 mL). After 1 h, the reaction mixture was diluted withEtOAc, was washed with NaHCO₃ (saturated, aqueous, 2×) and pH 7phosphate buffer (1×), was dried over Na₂SO₄, was filtered, and wasconcentrated under reduced pressure to give the crude compoundS16-6-4-2, which was used without further purification: MS (ESI) m/z937.49 (M+H).

Compound S16-6-2 (19.5 mg, 0.0218 mmol) was stirred in methanesulfonicacid (0.10 mL), dimethylsulfide (0.020 mL), and CH₂Cl₂ (0.20 ml). Afterstirring overnight, the reaction mixture was concentrated under a flowof air. Dimethylsulfide (0.020 mL), and CH₂Cl₂ (0.040 ml) were added,and the mixture was stirred overnight. Additional dimethylsulfide (0.040mL) was added, and the mixture was stirred for 5 h. The reaction mixturewas diluted with 0.05N aqueous HCl (2 mL) and was purified directly on aWaters Autopurification system equipped with a Phenomenex Polymerx 10μRP 100A column [10 μm, 30×21.20 mm; flow rate, 20 mL/min; Solvent A:0.05N HCl in water; Solvent B: CH₃CN; gradient: 0→50% B; mass-directedfraction collection]. Fractions with the desired MW were collected andfreeze-dried to yield 7.6 mg (57%) of S16-7-1 as a yellow solid (singlediastereomer): ¹H NMR (400 MHz, CD₃OD) δ 4.73 (s, 1H), 3.87 (s, 1H),3.70-3.60 (m, 1H), 3.40-3.30 (m, 1H), 3.12-3.00 (m, 1H), 2.99-2.82 (m,7H), 2.68-2.56 (m, 2H), 2.26-2.15 (m, 2H), 2.04-1.90 (m, 1H), 1.62-1.50(m, 1H); MS (ESI) m/z 503.11 (M+H).

The following compounds were prepared from S16-6-4-1 and S16-6-4-2according to the procedures for compound S16-7-1:

S16-7-2 (single diastereomer): ¹H NMR (400 MHz, CD₃OD) δ 4.73 (s, 1H),3.85 (s, 1H), 3.70-3.60 (m, 1H), 3.48-3.30 (m, 3H), 3.20-2.78 (m, 9H),2.65-2.56 (m, 1H), 2.24-2.14 (m, 2H), 2.04-1.90 (m, 1H), 1.60-1.49 (m,1H), 1.36 (t, J=7.3 Hz, 3H); MS (ESI) m/z 531.18 (M+H).

S16-7-3 (single diastereomer): ¹H NMR (400 MHz, CD₃OD) δ 4.76-4.70 (m,1H), 4.21 (s, 0.5H), 4.11 (s, 0.5H), 3.70-3.60 (m, 1H), 3.56-3.43 (m,1H), 3.40-3.30 (m, 2H), 3.11-2.84 (m, 12H), 2.65-2.56 (m, 1H), 2.27-2.13(m, 2H), 2.03-1.90 (m, 1H), 1.69-1.54 (m, 1H), 1.45-1.34 (m, 3H); MS(ESI) m/z 545.23 (M+H).

The following compounds were prepared according to the procedures forExample S16-7-1 substituting compound S16-5-2 for compound S16-5-1:

S16-7-4 (single diastereomer): ¹H NMR (400 MHz, CD₃OD) δ 4.76-4.70 (m,1H), 3.87 (s, 1H), 3.86-3.76 (m, 1H), 3.67 (dd, J=13.7, 5.04 Hz, 1H),3.48-3.24 (m, 4H), 3.07 (dd, J=14.2, 4.6 Hz, 1H), 3.00-2.85 (m, 1H),2.66-2.61 (m, 1H), 2.57-2.48 (m, 1H), 2.28-2.10 (m, 4H), 2.10-1.90 (m,3H), 1.63-1.52 (m, 1H); MS (ESI) m/z 529.14 (M+H).

S16-7-5 (single diastereomer): ¹H NMR (400 MHz, CD₃OD) δ 4.77-4.72 (m,1H), 3.87-3.77 (m, 2H), 3.67 (dd, J=13.7, 5.5 Hz, 1H), 3.50-3.26 (m,6H), 3.06 (dd, J=14.2, 4.6 Hz, 1H), 3.00-2.90 (m, 1H), 2.86-2.79 (m,1H), 2.57-2.49 (m, 1H), 2.28-2.12 (m, 4H), 2.11-1.90 (m, 3H), 1.60-1.48(m, 1H), 1.36 (t, J=7.3 Hz, 3H); MS (ESI) m/z 557.14 (M+H).

Compound S16-6-1 (116 mg, 0.119 mmol) and 2-mercaptobenzoic acid (22.0mg, 0.143 mmol) were weighed into a flask. This was evacuated andbackfilled with nitrogen (3×). THF (2 mL) was added followed by asolution of Pd(dba)₂ (6.9 mg, 0.012 mmol) and1,4-bis(diphenylphosphino)butane (5.1 mg, 0.012 mmol) in THF (0.20 mL).After 6 h, additional Pd(dba)₂ (6.9 mg, 0.012 mmol) and1,4-bis(diphenylphosphino)butane (5.1 mg, 0.012 mmol) in THF (0.20 mL)was added. After stirring overnight, the reaction mixture was dilutedwith EtOAc, was washed with NaHCO₃ (saturated, aqueous, 2×) and pH 7phosphate buffer (1×), was dried over Na₂SO₄, was filtered, and wasconcentrated under reduced pressure. The material was purified by columnchromatography (10 g Biotage column, 20 to 100% EtOAc in Hexanesgradient). This gave 33.9 mg (30%) of S16-6-3, 42.2 mg (36%) ofrecovered S16-6-1, and 19.5 mg (18%) of the fully de-allylated product,S16-6-2. MS for S16-6-3: (ESI) m/z 935.34 (M+H).

Formaldehyde (37% aqueous solution, 0.5 mL) was added to a mixture ofcompound S16-6-3 (33.9 mg, 0.0363 mmol) and Na(OAc)₃BH (23.0 mg, 0.109mmol) in CH₂Cl₂ (2 mL). After 1 h, ˜50% conversion was observed byLC/MS. Additional formaldehyde (37% aqueous solution, 0.5 mL) andNa(OAc)₃BH (25 mg, 0.12 mmol) were added. After stirring overnight,additional Na(OAc)₃BH (50 mg, 0.24 mmol) was added. After 2 h, thereaction mixture was diluted with EtOAc, was washed with NaHCO₃(saturated, aqueous, 3×) and pH 7 phosphate buffer (1×), was dried overNa₂SO₄, was filtered, and was concentrated under reduced pressure. Thecrude S16-6-4-3 was used without further purification: MS (ESI) m/z949.41 (M+H).

Compound S16-6-4-3 (34.4 mg, 0.0363 mmol), 1,3-dimethylbarbituric acid(22.7 mg, 0.145 mmol), and Pd(Ph₃P)₄ (4.2 mg, 0.0036 mmol) weredissolved in CH₂Cl₂ (4 mL), and the reaction mixture was evacuated andbackfilled with nitrogen (3×). After 6 h, the reaction mixture wasdiluted with EtOAc, was washed with NaHCO₃ (saturated, aqueous, 3×) andpH 7 phosphate buffer (1×), was dried over Na₂SO₄, was filtered, and wasconcentrated under reduced pressure. The material was purified by columnchromatography (10 g Biotage column, 50 to 100% EtOAc in Hexanesgradient). This gave 32.8 mg (99%) of S16-6-4-4: MS (ESI) m/z 909.36(M+H).

Compound S16-6-4-4 (32.8 mg, 0.0361 mmol) was stirred in methanesulfonicacid (0.10 mL), dimethylsulfide (0.020 mL), and CH₂Cl₂ (0.20 ml). Afterstirring overnight, the reaction mixture was concentrated.Dimethylsulfide (0.040 mL), and CH₂Cl₂ (0.040 ml) were added. After 4 h,the reaction mixture was diluted with 1:1 MeOH:0.05N aqueous HCl (2 mL)and was purified directly on a Waters Autopurification system equippedwith a Phenomenex Polymerx 10 RP 100A column [10 μm, 30×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05N HCl in water; Solvent B: CH₃CN;gradient: 0→50% B; mass-directed fraction collection]. Fractions withthe desired MW were collected and freeze-dried to yield 10.7 mg (47%) ofS16-7-6 as an orange-red solid (single diastereomer): ¹H NMR (400 MHz,CD₃OD) δ 4.76-4.71 (m, 1H), 3.81 (s, 1H), 3.68-3.60 (m, 1H), 3.42-3.32(m, 1H), 3.06 (dd, J=15.1, 4.6 Hz, 1H), 3.02-2.78 (m, 11H), 2.66-2.56(m, 1H), 2.24-2.12 (m, 2H), 2.04-1.92 (m, 1H), 1.58-1.46 (m, 1H); MS(ESI) m/z 517.22 (M+H).

The follow compounds were prepared according to Scheme 17.

Lithium diisopropylamide was prepared from diisopropylamine (0.0393 mL,0.278 mmol) and n-BuLi (1.6M solution, 0.174 mL, 0.278 mmol) in THF (3mL) at −40° C. The reaction mixture was cooled to −78° C., and TMEDA(0.128 mL, 0.856 mmol) was added. A solution of compound S17-1-1 (75.0mg, 0.235 mmol, prepared according to literature procedures including J.Med. Chem., 2011, 54, 1511) in THF (1 mL) was then added dropwise,resulting in a deep red solution. The reaction mixture was stirred at−78° C. for 30 min. A solution of enone S1-9-2 (114 mg, 0.214 mmol) inTHF (1 mL) was added dropwise, followed by LHMDS (1.0M solution, 0.257mL, 0.257 mmol). The reaction mixture was allowed to warm to −20° C.over 1 h. The reaction was quenched by the addition of ammonium chloride(saturated, aqueous solution) and was diluted with EtOAc. The mixturewas washed with water (3×), 1N aq. NaOH (3×), pH 7 phosphate buffer(1×), and brine (1×), was dried over Na₂SO₄, was filtered, and wasconcentrated under reduced pressure. The material was purified by columnchromatography (25 g Biotage column, 10 to 50% EtOAc in Hexanesgradient). This gave 28.6 mg (18%) of S17-2-1: ¹H NMR (400 MHz, CDCl₃) δ15.7 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.54-7.24 (m, 10H), 5.85-5.73(m, 2H), 5.37 (s, 2H), 5.32-5.04 (m, 6H), 4.06 (d, J=10.4 Hz, 1H),3.36-3.16 (m, 4H), 2.90-2.82 (m, 2H), 2.60-2.40 (m, 1H), 2.14-2.05 (m,1H), 1.64-1.50 (m, 1H), 1.30-1.20 (m, 1H), 0.81 (s, 9H), 0.24 (s, 3H),0.12 (s, 3H); MS (ESI) m/z 760.24 (M+H).

Compound S17-2-1 (28.6 mg, 0.0376 mmol), 1,3-dimethylbarbituric acid(23.4 mg, 0.150 mmol), and Pd(Ph₃P)₄ (4.3 mg, 0.0038 mmol) weredissolved in CH₂Cl₂ (2 mL), and the reaction mixture was evacuated andbackfilled with nitrogen (3×). After 5 h, the reaction mixture wasdiluted with EtOAc, was washed with NaHCO₃ (saturated, aqueous, 3×) andbrine (1×), was dried over Na₂SO₄, was filtered, and was concentratedunder reduced pressure. The material was purified by columnchromatography (10 g Biotage column, 50 to 100% EtOAc in Hexanesgradient). This gave 4.8 mg (19%) of S17-2-3: MS (ESI) m/z 680.18 (M+H).

Compound S17-2-3 (4.8 mg, 0.0706 mmol) was stirred in methanesulfonicacid (0.10 mL), dimethylsulfide (0.020 mL), and CH₂Cl₂ (0.20 ml). Afterstirring overnight, the reaction mixture was concentrated.Dimethylsulfide (0.040 mL), and CH₂Cl₂ (0.040 ml) were added. After 4 h,additional methanesulfonic acid (0.040 mL) was added, and the mixturewas stirred overnight. The reaction mixture was purified directly on aWaters Autopurification system equipped with a Phenomenex Polymerx RP100A column [10 μm, 30×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05NHCl in water; Solvent B: CH₃CN; gradient: 0→50% B; mass-directedfraction collection]. Fractions with the desired MW were collected andfreeze-dried to yield 3.0 mg (92%) of S17-3-1 as a yellow solid: ¹H NMR(400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.31 (s, 1H), 3.91 (s, 1H), 3.42-3.008(m, 2H), 2.80-2.65 (m, 1H), 2.34-2.24 (m, 2H), 1.70-1.60 (m, 1H); MS(ESI) m/z 388.03 (M+H).

Lithium diisopropylamide was prepared from diisopropylamine (0.107 mL,0.754 mmol) and n-BuLi (1.6M solution, 0.471 mL, 0.754 mmol) in THF (5mL) at −40° C. The reaction mixture was cooled to −78° C., and TMEDA(0.377 mL, 2.51 mmol) was added. A solution of compound S17-1-2 (239 mg,0.659 mmol, prepared according to literature procedures including J.Med. Chem., 2011, 54, 1511) in THF (2 mL) was then added dropwise,resulting in an orange-red solution. The reaction mixture was stirred at−78° C. for 30 min. A solution of enone S1-9-2 (336 mg, 0.628 mmol) inTHF (1 mL) was added dropwise, followed by LHMDS (1.0M solution, 0.816mL, 0.816 mmol). The reaction mixture was allowed to warm to −20° C.over 1 h. The reaction was quenched by the addition of ammonium chloride(saturated, aqueous solution) and was diluted with EtOAc. The mixturewas washed with water (3×) and brine (1×), was dried over Na₂SO₄, wasfiltered, and was concentrated under reduced pressure. The material waspurified by column chromatography (25 g Biotage column, 10 to 40% EtOAcin Hexanes gradient). This gave 338.5 mg (67%) of S17-2-2: ¹H NMR (400MHz, CDCl₃) δ 15.5 (s, 1H), 8.01 (s, 1H), 7.54-7.48 (m, 2 H), 7.45-7.24(m, 7H), 7.14-7.08 (m, 1H), 5.88-5.75 (m, 2H), 5.37 (s, 2H), 5.26-5.07(m, 6H), 4.12 (d, J=10.1 Hz, 1H), 3.40-3.18 (m, 4H), 3.01 (dd, J=15.3,4.9 Hz, 1H), 2.97-2.86 (m, 1H), 2.76 (s, 6H), 2.63 (t, J=15.3 Hz, 1H),2.57-2.50 (m, 1H), 2.48-2.36 (m, 1H), 2.19-2.12 (m, 1H), 0.80 (s, 9H),0.25 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 803.27 (M+H).

Compound S17-2-2 (149 mg, 0.185 mmol), 1,3-dimethylbarbituric acid (115mg, 0.740 mmol), and Pd(Ph₃P)₄ (21.4 mg, 0.0185 mmol) were dissolved inCH₂Cl₂ (5 mL), and the reaction mixture was evacuated and backfilledwith nitrogen (3×). After stirring overnight, the reaction mixture wasdiluted with EtOAc, was washed with NaHCO₃ (saturated, aqueous, 3×), pH7 phosphate buffer (1×), and brine (1×), was dried over Na₂SO₄, wasfiltered, and was concentrated under reduced pressure. The material waspurified by column chromatography (25 g Biotage column, 0 to 10% MeOH inEtOAc gradient). This gave 98.1 mg (73%) of S17-2-4: MS (ESI) m/z 723.21(M+H).

Compound S17-2-4 (78.5 mg, 0.109 mmol) and acetic acid (0.0124 mL, 0.217mmol) were dissolved in MeOH (2 mL), and the reaction mixture was cooledto 0° C. Na(OAc)₃BH (46 mg, 0.217 mmol) and acetaldehyde (50 wt %solution in EtOH, 0.0217 mL, 0.217 mmol) were added. After 10 min,complete conversion was observed by LC/MS. The reaction mixture wasquenched with NaHCO₃ (saturated, aqueous) and was diluted with EtOAc.The mixture was washed with NaHCO₃ (saturated, aqueous, 2×), pH 7phosphate buffer (1×), and brine (1×), was dried over Na₂SO₄, wasfiltered, and was concentrated under reduced pressure to give crudeproduct S17-2-6-1, which was used without further purification: MS (ESI)m/z 751.30 (M+H).

Formaldehyde (37% aqueous solution, 0.5 mL) was added to a mixture ofcompound S17-2-6-1 (20.4 mg, 0.0272 mmol) and Na(OAc)₃BH (17.3 mg,0.0816 mmol) in CH₂Cl₂ (2 mL). After 1 h, the reaction mixture wasdiluted with EtOAc, was washed with NaHCO₃ (saturated, aqueous, 2×), pH7 phosphate buffer (1×), and brine, was dried over Na₂SO₄, was filtered,and was concentrated under reduced pressure to give crude productS17-2-6-2, which was used without further purification: MS (ESI) m/z765.34 (M+H).

Compound S17-2-4 (19.6 mg, 0.0271 mmol) was stirred in methanesulfonicacid (0.10 mL), dimethylsulfide (0.020 mL), and CH₂Cl₂ (0.20 ml). Afterstirring overnight, the reaction mixture was concentrated.Dimethylsulfide (0.080 mL), and CH₂Cl₂ (0.040 ml) were added. Afterstirring overnight, the reaction mixture was concentrated and purifiedon a Waters Autopurification system equipped with a Phenomenex Polymerx10 RP 100A column [10 μm, 30×21.20 mm; flow rate, 20 mL/min; Solvent A:0.05N HCl in water; Solvent B: CH₃CN; gradient: 0→50% B; mass-directedfraction collection]. Fractions with the desired MW were collected andfreeze-dried to yield 1.78 mg (13%) of S17-3-2 as a yellow solid: ¹H NMR(400 MHz, CD₃OD) δ 8.17 (s, 1H), 3.92 (s, 1H), 3.24-3.04 (m, 8H),2.74-2.64 (m, 1H), 2.58 (t, J=14.6 Hz, 1H), 2.36-2.26 (m, 1H), 1.70-1.60(m, 1H); MS (ESI) m/z 431.08 (M+H).

The following compounds were prepared from S17-2-6-1 and S17-2-6-2according to the procedures for compound S17-3-2:

S17-3-3: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 3.92 (s, 1H), 3.46-3.30(m, 2H), 3.26-3.08 (m, 8H), 2.93-2.84 (m, 1H), 2.60 (t, J=14.6 Hz, 1H),2.36-2.26 (m, 1H), 1.70-1.60 (m, 1H), 1.37 (t, J=6.8 Hz, 3H); MS (ESI)m/z 459.13 (M+H).

S17-3-4: ¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 3.92 (d, J=34.4 Hz,1H), 3.58-3.44 (m, 1H), 3.43-3.28 (m, 1H), 3.24-3.12 (m, 8H), 3.06-2.93(m, 4H), 2.60 (t, J=13.7 Hz, 1H), 2.40-2.26 (m, 1H), 1.78-1.64 (m, 1H),1.47-1.34 (m, 3H); MS (ESI) m/z 473.15 (M+H).

The following compounds were prepared from S17-2-4 according to similarprocedures for S17-3-3:

S17-3-5: ¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 4.30 (s, 1H), 3.66-3.53(m, 1H), 3.53-3.42 (m, 2H), 3.40-3.30 (m, 1H), 3.24-3.12 (m, 8H),3.00-2.93 (m, 1H), 2.59 (t, J=15.1 Hz, 1H), 2.37-2.29 (m, 1H), 1.76-1.64(m, 1H), 1.41 (t, J=7.4 Hz, 6H); MS (ESI) m/z 487.13 (M+H).

S17-3-6: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 4.01 (s, 1H), 3.83(hept, J=6.4 Hz, 1H), 3.24-3.10 (m, 8H), 2.94-2.84 (m, 1H), 2.65-2.55(m, 1H), 2.38-2.28 (m, 1H), 1.70-1.60 (m, 1H), 1.46-1.34 (m, 6H); MS(ESI) m/z 473.11 (M+H).

Compound S17-3-7 was isolated as a side-product from the methanesulfonicacid deprotection step of S17-3-6. S17-3-7: ¹H NMR (400 MHz, CD₃OD) δ7.53 (s, 1H), 3.99 (s, 1H), 3.82 (hept, J=6.4 Hz, 1H), 3.36-3.26 (m,1H), 3.02 (s, 3H), 2.94-2.84 (m, 2H), 2.36-2.26 (m, 2H), 1.70-1.60 (m,1H), 1.41 (dd, J=15.1, 6.4 Hz, 6H); MS (ESI) m/z 459.05 (M+H).

Compound S17-2-2 (165 mg, 0.205 mmol) and 2-mercaptobenzoic acid (37.9mg, 0.246 mmol) were weighed into a flask. This was evacuated andbackfilled with nitrogen (3×). THF (2 mL) was added followed by asolution of Pd(dba)₂ (12 mg, 0.021 mmol) and1,4-bis(diphenylphosphino)butane (9.0 mg, 0.021 mmol) in THF (0.20 mL).After 4 h, the reaction mixture was diluted with EtOAc, was washed withNaHCO₃ (saturated, aqueous, 2×), pH 7 phosphate buffer (1×), and brine(1×), was dried over Na₂SO₄, was filtered, and was concentrated underreduced pressure. The material was purified by column chromatography (25g Biotage column, 20 to 100% EtOAc in Hexanes gradient). This gave 52.3mg (34%) of S17-2-5 and 17.0 mg (11%) of the fully de-allylated product,S17-2-4. Data for S17-2-5: MS (ESI) m/z 763.23 (M+H).

Formaldehyde (37% aqueous solution, 0.5 mL) was added to a mixture ofcompound S17-2-5 (26.1 mg, 0.0342 mmol) and Na(OAc)₃BH (21.7 mg, 0.103mmol) in CH₂Cl₂ (2 mL). Additional portions of Na(OAc)₃BH (22 mg, 0.11mmol) were added approximately every 10 min over the next 1 h (6 total).The reaction mixture was diluted with EtOAc, was washed with NaHCO₃(saturated, aqueous, 2×) and brine (1×), was dried over Na₂SO₄, wasfiltered, and was concentrated under reduced pressure to yield the crudeproduct S17-2-6-3, which was used without further purification: MS (ESI)m/z 777.24 (M+H).

Compound S17-2-6-3 (13.3 mg, 0.0171 mmol) was stirred in aqueous HF(48-50% solution, 0.40 mL) and 1,4-dioxane (1 ml). After stirringovernight, the reaction mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL) and was extracted with EtOAc (2×). The organicswere concentrated and re-dissolved in MeOH (1 mL), 1,4-dioxane (1 mL),and 6N aqueous HCl (0.2 mL). 10% Pd on carbon (Degussa, 5 mg) was added,and an atmosphere of hydrogen (balloon) was introduced. After 1 h, thereaction mixture was purged with nitrogen and filtered through Celite(MeOH wash). The filtrate was concentrated and was purified on a WatersAutopurification system equipped with a Phenomenex Polymerx 10 RP 100Acolumn [10 μm, 30×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HClin water; Solvent B: CH₃CN; gradient: 0→50% B; mass-directed fractioncollection]. Fractions with the desired MW were collected andfreeze-dried to yield 2.4 mg (25%) of S17-3-8 as a yellow solid: ¹H NMR(400 MHz, CD₃OD) δ 4.76-4.71 (m, 1H), 3.81 (s, 1H), 3.68-3.60 (m, 1H),3.42-3.32 (m, 1H), 3.06 (dd, J=15.1, 4.6 Hz, 1H), 3.02-2.78 (m, 11H),2.66-2.56 (m, 1H), 2.24-2.12 (m, 2H), 2.04-1.92 (m, 1H), 1.58-1.46 (m,1H); MS (ESI) m/z 487.17 (M+H).

Compound S17-2-2 (16.4 mg, 0.0204 mmol) was stirred in aqueous HF(48-50% solution, 0.40 mL) and 1,4-dioxane (1 ml). After 2 h, thereaction mixture was poured into a solution of K₂HPO₄ (4.8 g) in water(20 mL) and was extracted with EtOAc (2×). The organics wereconcentrated and re-dissolved in MeOH (2 mL), 1,4-dioxane (2 mL), and 6Naqueous HCl (0.2 mL). 10% Pd on carbon (Degussa, 5 mg) was added, and anatmosphere of hydrogen (balloon) was introduced. After 1 h, the reactionmixture was purged with nitrogen and filtered through Celite (MeOHwash). The filtrate was concentrated and was purified on a WatersAutopurification system equipped with a Phenomenex Polymerx 10 RP 100Acolumn [10 μm, 30×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HClin water; Solvent B: CH₃CN; gradient: 0→50% B; mass-directed fractioncollection]. Fractions with the desired MW were collected andfreeze-dried to yield 0.88 mg (7%) of S17-3-9 as a yellow solid and 6.8mg (61%) of the mono-propyl compound S17-3-10. Data for S17-3-9: ¹H NMR(400 MHz, CD₃OD) δ 8.14 (s, 1H), 4.26 (s, 1H), 3.65-3.45 (m, 4H),3.24-2.90 (m, 9H), 2.54 (t, J=14.6 Hz, 1H), 2.32-2.20 (m, 1H), 1.94-1.60(m, 5H), 1.12-0.92 (m, 6H); MS (ESI) m/z 515.21 (M+H).

S17-3-10: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 3.93 (s, 1H),3.26-3.08 (m, 10H), 2.96-2.88 (m, 1H), 2.59 (t, J=14.6 Hz, 1H),2.37-2.27 (m, 1H), 1.84-1.72 (m, 2H), 1.70-1.60 (m, 1H), 1.03 (t, J=7.8Hz, 3H); MS (ESI) m/z 473.12 (M+H).

Lithium diisopropylamide was prepared from diisopropylamine (0.024 mL,0.167 mmol) and n-BuLi (1.84M solution, 0.091 mL, 0.167 mmol) in THF (2mL) at −40° C. The reaction mixture was cooled to −78° C., and TMEDA(0.091 mL, 0.608 mmol) was added. A solution of compound S17-1-2 (55.3mg, 0.152 mmol) in THF (0.5 mL) was then added dropwise, resulting in adeep orange solution. The reaction mixture was stirred at −78° C. for 5min. A solution of enone S2-7-3 (40 mg, 0.076 mmol) in THF (0.5 mL) wasadded dropwise. The reaction mixture was allowed to warm to −20° C. over45 min. The reaction was quenched by the addition of ammonium chloride(saturated, aqueous solution) and was extracted with EtOAc (2×). Thecombined extracts were dried over Na₂SO₄, were filtered, and wereconcentrated under reduced pressure. The material was purified bypreparative reverse phase HPLC purification on a Waters Autopurificationsystem using a Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate,20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1%HCO₂H; gradient: 80→100% B over 15 min; mass-directed fractioncollection]. This gave 28.9 mg (48%) of S17-2-7: ¹H NMR (400 MHz, CDCl₃)δ 15.5 (s, 1H), 8.02 (s, 1H), 7.52-7.22 (m, 10H), 5.36 (s, 2H),5.22-5.12 (m, 2H), 4.03 (d, J=10.4 Hz, 1H), 3.74-3.70 (m, 4H), 3.12-2.86(m, 4H), 2.72 (s, 6H), 2.66-2.54 (m, 4H), 2.51-2.38 (m, 1H), 2.24-2.16(m, 1H), 0.81 (s, 9H), 0.25 (s, 3H), 0.13 (s, 3H); MS (ESI) m/z 793.45(M+H).

Compound S17-2-7 (28.9 mg, 0.0364 mmol) was stirred in aqueous HF(48-50% solution, 0.40 mL) and acetonitrile (0.6 ml). After stirringovernight, the reaction mixture was poured into a solution of K₂HPO₄(4.8 g) in water (15 mL) and was extracted with EtOAc (3×). The organicswere dried over Na₂SO₄, were filtered, and were concentrated. Thematerial was dissolved in MeOH (1 mL) and 1,4-dioxane (1 mL), 10% Pd oncarbon (Degussa, 5 mg) was added, and an atmosphere of hydrogen(balloon) was introduced. After 2 h, the reaction mixture was purgedwith nitrogen and filtered through Celite (MeOH wash). The filtrate wasconcentrated and was purified on a Waters Autopurification systemequipped with a Phenomenex Polymerx 10μ RP 100A column [10 μm, 30×21.20mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl in water; Solvent B:CH₃CN; gradient: 0→100% B; mass-directed fraction collection]. Fractionswith the desired MW were collected and freeze-dried to yield 12.6 mg(60%) of S17-3-11 as an orange solid: ¹H NMR (400 MHz, CD₃OD) δ 8.21 (s,1H), 4.21 (s, 1H), 4.12-3.94 (m, 3H), 3.93-3.74 (m, 2H), 3.70-3.52 (m,3H), 3.34-3.18 (m, 9H), 2.61 (t, J=14.6 Hz, 1H), 2.43-2.35 (m, 1H),1.74-1.62 (m, 1H); MS (ESI) m/z 501.29 (M+H).

The following compounds were prepared according to Scheme 18.

Lithium diisopropylamide was prepared from diisopropylamine (0.0807 mL,0.571 mmol) and n-BuLi (2.5M solution, 0.228 mL, 0.571 mmol) in THF (10mL) at −40° C. The reaction mixture was cooled to −78° C., and TMEDA(0.367 mL, 2.45 mmol) was added. A solution of compound S18-1 (240 mg,0.489 mmol, prepared according to literature procedures includingWO2011123536) in THF (5 mL) was added dropwise, resulting in a deep redsolution. The reaction mixture was stirred at −78° C. for 5 min. Asolution of enone S2-7-2 (208 mg, 0.408 mmol) in THF (2 mL) was addeddropwise. The reaction mixture was allowed to warm to −20° C. over 1 h.The reaction was quenched by the addition of ammonium chloride(saturated, aqueous solution) and was extracted with EtOAc (2×). Thecombined extracts were dried over Na₂SO₄, were filtered, and wereconcentrated under reduced pressure. The material was purified by columnchromatography (25 g Biotage column, 5 to 40% EtOAc in Hexanesgradient). This gave 198 mg (54%) of S18-2: ¹H NMR (400 MHz, CDCl₃) δ15.96 (s, 1H), 7.55 (d, J=6.7 Hz, 2H), 7.48 (d, J=6.7 Hz, 2H), 7.40-7.29(m, 6H), 5.78 (s, 1H), 5.35 (s, 2H), 4.95 (ABq, J=26.2, 9.2 Hz, 2H),4.19 (d, J=10.4 Hz, 1H), 3.52 (s, 6H), 3.21 (dd, J=16.5, 5.5 Hz, 1H),3.07-2.92 (m, 3H), 2.70-2.58 (m, 3H), 2.48-2.32 (m, 2H), 2.15-2.08 (m,1H), 1.88-1.80 (m, 4H), 0.80 (s, 9H), 0.25 (s, 3H), 0.12 (s, 3H); MS(ESI) m/z 903.25, 905.25 (M+H).

Compound S18-2 (198 mg, 0.219 mmol) was dissolved in THF (5 mL), and 6Naqueous HCl (0.5 mL) was added. After 4 h, the reaction mixture wasconcentrated under reduced pressure to give crude S18-3, which was usedfor the next step without further purification: MS (ESI) m/z 857.23,859.20 (M+H).

Compound S18-3 (78.2 mg, 0.0874 mmol) was dissolved in CH₂Cl₂ (4 mL).HOAc (0.015 mL, 0.262 mmol) and 2,2-dimethylpropan-1-amine (22.8 mg,0.262 mmol) were added. The mixture was stirred for 30 min, andNa(OAc)₃BH (37 mg, 0.175 mmol) was added. After stirring overnight, thereaction mixture was diluted with pH 7.4 phosphate buffer and wasextracted with CH₂Cl₂ (3×). The combined extracts were dried overNa₂SO₄, were filtered, and were concentrated to give crude S18-4-1,which was used for the next step without further purification: MS (ESI)m/z 928.32, 930.35 (M+H).

Compound S18-4-1 (crude, 0.0874 mmol) was stirred in aqueous HF (48-50%solution, 0.40 mL) and 1,4-dioxane (1 mL). After stirring overnight, thereaction mixture was poured into a solution of K₂HPO₄ (4.8 g) in water(15 mL) and was extracted with EtOAc (2×). The organics were dried overNa₂SO₄, were filtered, and were concentrated. The material was dissolvedin MeOH (2 mL) and 1,4-dioxane (2 mL), and 10% Pd—C (5 mg) was added. Anatmosphere of hydrogen (balloon) was introduced, and 0.5M HCl in MeOH(0.2 mL) was added. After 2 h, the reaction mixture was purged withnitrogen and was filtered through Celite. The filtrate was concentrated,and the material was purified on a Waters Autopurification systemequipped with a Phenomenex Polymerx 10 p RP 100A column [10 μm, 30×21.20mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl in water; Solvent B:CH₃CN; gradient: 20→100% B; mass-directed fraction collection].Fractions with the desired MW were collected and freeze-dried to yield30.5 mg (55%) of S18-5-1-1 as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ7.13 (d, J=5.5 Hz, 1H), 4.33 (s, 2H), 4.09 (s, 1H), 4.00-3.90 (m, 1H),3.80-3.68 (m, 1H), 3.60-3.40 (m, 2H), 3.28-3.02 (m, 3H), 2.92 (s, 2H),2.38-1.95 (m, 6H), 1.68-1.54 (m, 1H), 1.06 (s, 9H); MS (ESI) m/z 558.31(M+H).

The following Example was prepared according to procedures similar tothose described for Example S18-5-1-1:

S18-5-1-2: ¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.22 (s,2H), 4.09 (s, 1H), 3.98-3.88 (m, 1H), 3.78-3.68 (m, 1H), 3.60-3.40 (m,2H), 3.28-3.00 (m, 3H), 2.38-1.95 (m, 6H), 1.66-1.54 (m, 1H), 1.47 (s,9H); MS (ESI) m/z 544.28 (M+H).

Compound S18-5-1-1 (11.6 mg, 0.0184 mmol) was dissolved in DMF (0.5 mL)and triethylamine (0.0051 mL, 0.0368 mmol), InCl₃ (0.41 mg, 0.0018mmol), and formaldehyde (0.0041 mL, 0.0552 mmol) were added. After 30min, the reaction mixture was diluted with 0.5M HCl in MeOH (0.5 mL) andwas added dropwise to diethyl ether (125 mL). The resulting solid wascollected by filtration through Celite (diethyl ether wash, 3×). Thesolid was dissolved in MeOH and was concentrated. The material waspurified on a Waters Autopurification system equipped with a PhenomenexPolymerx 10 RP 100A column [10 μm, 30×21.20 mm; flow rate, 20 mL/min;Solvent A: 0.05N HCl in water; Solvent B: CH₃CN; gradient: 20→100% B;mass-directed fraction collection]. Fractions with the desired MW werecollected and freeze-dried to yield 2.9 mg (24%) of S18-5-2-1 as ayellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.56 (d,J=12.8 Hz, 1H), 4.33 (d, J=12.8 Hz, 1H), 3.99 (s, 1H), 3.98-3.90 (m,1H), 3.78-3.65 (m, 1H), 3.51-3.36 (m, 2H), 3.25-3.10 (m, 2H), 3.10-2.90(m, 5H), 2.46-2.32 (m, 1H), 2.26-1.94 (m, 6H), 1.70-1.58 (m, 1H), 1.07(s, 9H); MS (ESI) m/z 572.31 (M+H).

The following Example was prepared according to procedures similar tothose described for Example S18-5-2-1:

S18-5-2-2: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.17 (m, 1H), 4.13-4.02 (m,3H), 3.90-3.78 (m, 1H), 3.62-3.50 (m, 2H), 3.35-28 (m, 1H), 3.23-3.09(m, 1H), 2.92-2.80 (m, 4H), 2.56-2.42 (m, 1H), 2.38-2.03 (m, 6H),1.80-1.60 (m, 10H); MS (ESI) m/z 558.34 (M+H).

The following compounds were prepared according to Schemed 19.

To a solution of i-Pr₂NH (0.56 mL, 3.97 mmol, 1.5 eq) in THF (25 mL) wasadded n-BuLi (2.34 mL, 1.7M/hexanes, 3.97 mmol, 1.5 eq) drop wise at−78° C. The reaction was allowed to warm to 0° C. and then cooled to−78° C. A solution of ester S19-1 (1.10 g, 2.65 mmol, 1 eq, preparedaccording to literature procedures including WO2011123536) in THF (3 mL)was added at −78° C., and the mixture was stirred for 25 min. A solutionof N-Boc-2-pyrrolidinone (1.23 g, 6.63 mmol, 2.5 eq) in THF (3 mL) wasadded at −78° C. The reaction mixture was stirred at −78° C. for 25 min,slowly warmed to −30° C., and stirred at −30° C. for 20 min. Thereaction was quenched with aqueous phosphate buffer (5 mL, pH=7). Themixture was extracted with EtOAc (3×15 mL). The organic extracts werecombined, dried over Na₂SO₄, and concentrated. The residue was purifiedby flash chromatography on silica gel, eluting with hexanes/EtOAc (1:0to 7:1) to afford S19-2 (800 mg, 50%): ¹H NMR (400 MHz, CDCl₃) δ7.24-7.50 (m, 8H), 7.01-7.06 (m, 2H), 5.09 (s, 2H), 4.61-4.70 (br, 1H),3.20-3.27 (m, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.34 (d, J=1.8 Hz, 3H), 1.94(dq, J=6.7, 6.7 Hz, 2H), 1.43 (s, 9H); MS (ESI) m/z 624.44 (M+Na).

To a solution of ketone S19-2 (800 mg, 1.33 mmol) in CH₂Cl₂ (8 mL) wasadded TFA (2 mL). The reaction mixture was stirred at rt for 1 h andconcentrated. A solution of K₂CO₃ (5.0 g) in water (10 mL) was added,and the mixture was extracted with EtOAc (3×10 mL). The organic layerswere combined, dried over Na₂SO₄, and concentrated. The residue wasre-dissolved in toluene/EtOAc (1:1, 25 mL), stirred at 60° C. for 20 h,and concentrated. The residue was purified by flash chromatography onsilica gel, eluting with hexanes/EtOAc (1:0 to 3:1) to afford S19-3 (600mg, 93%): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.50 (m, 8H), 7.02-7.07 (m,2H), 5.10 (s, 2H), 4.12-4.17 (m, 2H), 2.82-2.89 (m, 2H), 2.34 (d, J=2.4Hz, 3H), 2.06-2.15 (m, 2H); MS (ESI) m/z 480.31 (M−H).

To a solution of S19-3 (500 mg, 1.04 mmol, 1 eq) in THF (20 mL) wasadded i-PrMgBr—LiCl (3.50 mL, 1.2M/THF, 4.16 mmol, 4 eq) at −50° C. Thereaction mixture was slowly warmed to 0° C. over 1 h and stirred at 0°C. for 2 h. The reaction mixture was added with aqueous phosphate buffer(10 mL, pH=7) and extracted with EtOAc (100 mL). The organic extract waswashed with brine (3×20 mL), dried over Na₂SO₄, and concentrated todryness to give intermediate S19-4.

S19-4 was re-dissolved in CH₃OH (20 mL) and added with NaBH₄ (100 mg,2.64 mmol, 2.5 eq). The solution was stirred at rt for 40 min.HCl/1,4-dioxane (4 mL, 4N) was added. The mixture was stirred at rt for10 min and concentrated. Aqueous NaOH (10 mL, 1N) was added. The aqueouslayer was extracted with EtOAc (3×15 mL). The organic extracts werecombined, dried over Na₂SO₄, and concentrated. The residue was purifiedby flash chromatography on silica gel, eluting with hexanes/EtOAc (1:0to 0:1) to afford S19-5-1 (330 mg, 79% over 2 steps): ¹H NMR (400 MHz,CDCl₃) δ 7.05-7.45 (m, 11H), 5.13 (s, 2H), 4.41 (t, J=7.6 Hz, 1H),3.01-3.18 (m, 2H), 2.34 (d, J=1.8 Hz, 3H), 2.20-2.32 (m, 1H), 1.52-1.80(comp, 3H); MS (ESI) m/z 405.97 (M+H).

To a solution of S19-5-1 (350 mg, 0.864 mmol, 1 eq) in dichloroethane (5mL) was added aqueous formaldehyde (37%, 322 μL, 4.32 mmol, 5 eq),followed by acetic acid (247 μL, 4.32 mmol, 5 eq). After 10 min, sodiumtriacteoxyborohydride (905 mg, 4.27 mmol, 5 eq) was added. After 110min, the reaction solution was diluted slowly with aqueous sodiumbicarbonate solution (4 mL) and stirred 20 min, then was diluted furtherwith aqueous sodium bicarbonate solution (20 mL), water (5 mL) andextracted with EtOAc (2×50 mL). The combined organic layers were driedover Na₂SO₄, were filtered, and were concentrated under reducedpressure. Purification of the resulting residue via flash columnchromatography (Biotage, 25 g silica gel column, 20% to 60% EtOAc inhexanes gradient) provided the desired compound S19-5-2 (292 mg, 80%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.40 (m, 2H), 7.39-7.27(m, 5H), 7.25-7.22 (m, 1H), 7.12-7.02 (m, 1H), 5.15 (s, 2H), 3.46 (t,J=7.9 Hz, 1H), 3.25 (t, J=7.9 Hz, 1H), 2.35 (s, 3H), 2.33-2.24 (m, 2H),2.20 (s, 3H), 1.98-1.78 (m, 2H), 1.69-1.50 (m, 1H); MS (ESI) m/z 418.27(M−H).

Lithium diisopropylamide (3.2 eq) was prepared at −40° C. fromn-butyllithium (1.6M solution in hexane, 1.23 mL, 1.96 mmol) anddiisopropylamine (287 μL, 2.03 mmol) in THF (15 mL). The solution wascooled to −78° C. and TMEDA (304 μL, 2.03 mmol, 3.2 eq) was added,followed by drop wise addition of compound S19-5-1 (766 mg, 1.89 mmol,3.0 eq) in THF (2 mL) with a 500 μL THF rinse forward, maintaininginternal temp below −70° C. The solution became a deep red color. After30 min at this temperature, a solution of diallylenone S1-9-2 (339 mg,0.634 mmol, 1 eq) in THF (2 mL) was added drop wise via syringe with a500 μL THF rinse forward. After complete addition, the reaction mixturewas allowed to warm over 75 min. Excess base was quenched at −10° C. bythe addition of saturated aqueous NH₄Cl (6 mL). The reaction mixture wasdiluted with pH 7 phosphate buffer (40 mL) and extracted with EtOAc(2×40 mL). Combined organic extracts were dried over Na₂SO₄, werefiltered, and were concentrated under reduced pressure. The material waspurified on a Waters Autopurification system equipped with a SunfirePrep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A:H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; gradient: 40→60%B; mass-directed fraction collection], yielding 89.8 mg of an earlyeluting diastereomer (S19-6-1-A: diastereomer A), 120 mg of a latereluting diastereomer ((S19-6-1-B: diastereomer B), and 34 mg of adiastereomeric mixture (45% total yield). S19-6-1-A: ¹H NMR(diastereomer A: 400 MHz, CDCl₃) δ 7.52-7.46 (m, 4H), 7.41-7.30 (m, 5H),7.28-7.25 (m, 1H), 7.14 (d, J=5.5 Hz, 1H), 5.87-5.72 (m, 2H), 7.36 (s,2H), 5.25-5.12 (m, 4H), 5.10 (d, J=10.4 Hz, 2H), 4.43 (t, J=7.9 Hz, 1H),4.07 (d, J=7.9 Hz, 1H), 3.36-3.28 (m, 2H), 3.25-3.02 (m, 5H), 2.99-2.91(m, 1H), 2.62-2.53 (m, 1H), 2.52-2.48 (m, 2H), 2.32-2.21 (m, 1H),2.16-2.08 (m, 1H), 1.89-1.80 (m, 2H), 1.67-1.57 (m, 1H), 0.81 (s, 9H),0.24 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 846.54 (M+H). S19-6-1-B: ¹H NMR(diastereomer B: 400 MHz, CDCl₃) δ 7.57-7.47 (m, 4H), 7.40-7.22 (m, 7H),5.84-5.73 (m, 2H), 5.37 (s, 2H), 5.36 (s, 2H), 5.16 (d, J=16.5 Hz, 2H),5.11 (d, J=9.8 Hz, 2H), 4.75 (t, J=7.9 Hz, 1H), 4.04 (d, J=10.3 Hz, 1H,3.43-3.34 (m, 1H), 3.42-3.08 (m, 6H), 3.03-2.91 (m, 1H), 2.66-2.53 (m,1H), 2.52-2.30 (m, 3H), 2.14-2.07 (m, 1H), 2.02-1.82 (m, 3H), 0.82 (s,9H), 0.24 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 846.54 (M+H).

A solution of S19-6-1-B (13 mg, 0.016 mmol, 1 eq),tetrakis(triphenylphosphine)-palladium (1.8 mg, 0.0016 mmol, 0.1 eq) anddimethylbarbituric acid (12.3 mg, 0.079 mmol, 5 eq) in dichloromethane(750 μL) was degassed with bubbling nitrogen gas for two minutes andthen stirred at ambient temperature for 17 h. Additional solvent (1 mL)and Pd catalyst (3 mg, 0.25 mmol, 0.2 eq) were added and the solutiondegassed as above. After an additional 42 h, the reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution (15 mL) andextracted with EtOAc (2×20 mL). The organic layer was dried over Na₂SO₄,was filtered, and was concentrated under reduced pressure. Purificationof the resulting residue via flash column chromatography (Biotage, 10 gsilica gel column, 1% to 10% MeOH in dichloromethane gradient) providedthe desired compound S19-6-4-1-B (4.8 mg, 40%, diastereomer B): ¹H NMR(400 MHz, CDCl₃) δ 7.60-7.41 (m, 4H), 7.40-7.23 (m, 6H), 7.18-7.12 (m,1H), 5.43-5.32 (m, 2H), 5.28-5.14 (m, 2H), 4.42-4.36 (m, 1H), 3.91 (brs,1H), 3.14-2.98 (m, 2H), 2.83-2.72 (m, 1H), 2.64-2.58 (m, 1H), 2.30-2.02(m, 2H), 1.87-1.77 (m, 2H), 1.24 (brs, 1H), 0.90-0.82 (m, 1H), 0.75 (s,9H), 0.20 (s, 3H), 0.09 (s, 3H); MS (ESI) m/z 766.47 (M+H).

A solution of S19-6-1-B (4.8 mg, 0.0063 mmol) in dichloromethane (200μL) was cooled to 0° C. was added dimethylsulfide (10 μL), followed bydrop wise addition of methanesulfonic acid. The reaction mixture wasallowed to warm and was stirred at ambient temperature for 21 h.Dichloromethane solvent was evaporated under an N₂ stream, another 50 μLof dichloromethane and 10 μL of dimethylsulfide were added. After anadditional 5 d, the solvent was evaporated and the resulting red-orangeresidue was purified on a Waters Autopurification system equipped with aPhenomenex Polymerx 10 RP 100A column [10 μm, 30×21.20 mm; flow rate, 20mL/min; Solvent A: 0.05N HCl in water; Solvent B: CH₃CN; gradient: 0→30%B; mass-directed fraction collection]. Fractions with the desired MWwere collected and freeze-dried to yield the desired compound S19-7-1-B(1.4 mg, 42%) as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ6.97 (d, J=5.5Hz, 1H), 3.88 (s, 1H), 3.53-3.39 (m, 2H), 3.22-3.16 (m, 1H), 3.08-2.96(m, 1H), 2.71-2.62 (m, 2H), 2.58-2.45 (m, 1H), 2.40-2.12 (m, 5H),2.67-2.53 (m, 1H); MS (ESI) m/z 474.10 (M+H).

To a solution of S19-6-1-A (diastereomer A, 89.8 mg, 0.106 mmol, 1 eq)in dichloromethane (1 mL) was added di-tert-butyl dicarbonate (28.5 mg,0.130 mmol, 1.2 eq) and dimethylaminopyridine (1.3 mg, 0.011 mmol, 0.1eq) and the reaction mixture was stirred at ambient temperature. After70 min, the mixture was placed in the fridge (4° C.) overnight, thendiluted with saturated aqueous ammonium chloride (10 mL), water (2 mL)and extracted with EtOAc (2×20 mL). The combined organic layers weredried over Na₂SO₄, were filtered, and were concentrated under reducedpressure. Purification of the resulting residue via flash columnchromatography (Biotage, 10 g silica gel column, 5% to 40% EtOAc inhexanes gradient) provided the desired compound S19-6-3-A (80.7 mg, 80%)as an oil. Similar conditions were applied to S19-6-1-B (diastereomer B,120 mg, 0.142 mmol) to provide 58 mg of desired S19-6-3-B (43%).S19-6-3-A: ¹H NMR (diastereomer A, rotamers: 400 MHz, CDCl₃) δ 16.05 (m,1H), 7.52-7.25 (m, 10H), 6.66-6.51 (m, 1H), 5.87-5.72 (m, 2 H), 5.36 (s,2H), 5.25-4.90 (m, 6H), 3.65-2.88 (m, 8H), 2.63-2.17 (m, 3H), 2.15-2.07(m, 1H), 1.88-1.62 (m, 2H), 1.47, 1.19 (m, 9H), 0.81 (s, 9H), 0.24 (s,3H), 0.12 (s, 3H); MS (ESI) m/z 946.64 (M+H). S19-6-3-B: ¹H NMR(diastereomer B, rotamers: 400 MHz, CDCl₃) δ 7.53-7.25 (m, 10H),6.49-6.41 (m, 1H), 5.35 (s, 2H), 5.25-4.89 (m, 6H), 3.57-3.01 (m, 8H),2.67-2.37 (m, 3H), 2.29-2.15 (m, 1H), 1.48-1.10 (m, 9H), 0.88-0.79 (m,9H), 0.27-0.09 (m, 6H); MS (ESI) m/z 946.67 (M+H).

To a solution of S19-6-3-A (diastereomer A, 80.7 mg, 0.085 mmol, 1 eq)and 2-mercaptobenzoic acid (15.8 mg, 0.102 mmol, 1.2 eq) in THF (1 mL)under N₂ was added 100 μL of a dry, air-free prepared solution ofbis(dibenzylideneacetone)palladium(0) and1,4-bis(diphenylphosphinebutane) in THF (0.086M of catalyst/ligand, 1mL) drop wise via syringe. After 24 h, another aliquot ofcatalyst/ligand solution was added. After an additional 28 h, thereaction mixture was diluted with saturated aqueous sodium bicarbonatesolution (10 mL) and pH 7 phosphate buffer (15 mL) and extracted withEtOAc (2×20 mL). The combined organic layers were dried over Na₂SO₄,were filtered, and were concentrated under reduced pressure.Purification of the resulting residue via flash column chromatography(Biotage, 10 g silica gel column, 7% to 60% EtOAc in hexanes gradient)provided the monoallyl compound S19-6-6-2-A (25 mg, 32%), the aminocompound S19-6-6-1-A (12.5 mg, 17%) and recovered diallyl startingmaterial S19-6-3-A (26.5 mg, 33%). Similar conditions were applied toS19-6-3-B (diastereomer B, 58 mg, 0.061 mmol) to provide monoallylS19-6-6-2-B (15.3 mg, 28%), amino S19-6-6-1-B (10.7 mg, 20%), andrecovered diallyl S19-6-3-B (19.3, 33%). Monoallyl S19-6-6-2-A: ¹H NMR(diastereomer A, 400 MHz, CDCl₃, rotamers) δ 16.71-16.56 (m, 1H),7.45-7.20 (m, 10H), 6.56-6.42 (m, 1H), 5.36-5.27 (m, 2H), 5.26-4.83 (m,4H), 3.67-3.21 (m, 4H), 2.97-2.85 (m, 1H), 3.78-3.62 (m, 1H), 3.58-2.90(m, 4H), 2.87-2.59 (m, 2H), 2.58-1.09 (m, 11H), 0.82-0.58 (m, 9H),0.21-0.12 (m, 3H), 0.09-0.05 (m, 3H); MS (ESI) m/z 906.59 (M+H). AminoS19-6-6-1-A: ¹H NMR (diastereomer A, 400 MHz, CDCl₃, rotamers); MS (ESI)m/z 866.57 (M+H). Monoallyl S19-6-6-2-B: ¹H NMR (diastereomer B, 400MHz, CDCl₃, rotamers) δ 7.48-7.23 (m, 10H, 6.37-6.29 (m, 1H), 5.91-5.74(m, 1H), 5.36-4.81 (m, 6H), 377-2.62 (m, 6H), 2.31-2.03 (m, 2H),1.70-1.07 (m, 15H), 0.83-0.62 (m, 9H), 0.26-0.15 (m, 3H), 0.04-0.23 (m,3H); MS (ESI) m/z 906.59 (M+H). Amino S19-6-6-1-B: ¹H NMR (diastereomerB, 400 MHz, CDCl₃, rotamers); MS (ESI) m/z 866.57 (M+H).

To a solution of S19-6-6-1-A (diastereomer A, 12.5 mg, 0.014 mmol, 1 eq)in methanol (750 μL) was added acetic acid (4 μL, 0.072 mmol, 3 eq) andthe mixture cooled to 0° C. Sodium triacetoxyborohydride (12.3 mg, 0.058mmol, 4 eq) was added, followed by a prepared solution of acetaldehydein methanol (50 μL in 950 μL; 48 μL, 0.043 mmol, 3 eq). After 50 min at0° C., the solution was diluted with saturated aqueous sodiumbicarbonate solution (1 mL), pH 7 phosphate buffer (1 mL) and EtOAc (500μL). Stirred 5 min, then extracted with EtOAc (10 mL, 5 mL). Combinedorganic layers were dried over Na₂SO₄, were filtered, and wereconcentrated under reduced pressure. The resulting crude oil,S19-6-9-1-A, was used without further purification: MS (ESI) m/z 894.40(M+H). Similar results observed with diastereomer B S19-6-6-1-B and adiastereomeric mixture of S19-6-6-1.

S19-7-2 (diastereomeric mixture) was prepared similarly to compoundS19-7-1-B from S19-6-9-1 (diastereomeric mixture) via treatment withdimethylsulfide in methanesulfonic acid: ¹H NMR (400 MHz, CD₃OD)δ7.01-6.95 (m, 1H), 3.87 (s, 1H), 3.57-3.38 (m, 5H), 3.19 (dd, J=15.9,4.3 Hz, 1H), 3.08-2.92 (m, 1H), 2.88-2.81 (m, 1H), 2.55-2.46 (m, 1H),2.41-2.07 (5H), 1.64-1.50 (m, 1H), 1.45-1.32 (m, 3H); MS (ESI) m/z502.13 (M+H).

To a solution of S19-6-9-1-A (diastereomer A, 0.014 mmol, 1 eq) indichloroethane (750 μL) was added aqueous formaldehyde (37%, 5.6 μL,0.072 mmol, 5 eq), followed by acetic acid (4 μL, 0.072 mmol, 5 eq).After fifteen minutes, sodium triacteoxyborohydride (14.8 mg, 0.072mmol, 5 eq) was added. After 70 min, the reaction solution was dilutedwith aqueous sodium bicarbonate solution (1 mL) and stirred fiveminutes, then diluted further with aqueous sodium bicarbonate solution(6 mL) and extracted with EtOAc (2×8 mL). The combined organic layerswere dried over Na₂SO₄, were filtered, and were concentrated underreduced pressure. The resulting crude oil, S19-6-9-2-A, was used withoutfurther purification. S19-6-9-2-B (diastereomer B) was preparedsimilarly to compound S19-6-9-2-A from S19-6-9-1-B (diastereomer B) viareductive alkylation as above. S19-6-9-2-A: MS (ESI) m/z 908.60 (M+H).S19-6-9-2-B: MS (ESI) m/z 908.61 (M+H).

To a solution of S19-6-6-2-A (diastereomer A, 15.3 mg, 0.017 mmol, 1 eq)in dichloroethane (1.5 mL) was added aqueous formaldehyde (37%, 6.3 μL,0.084 mmol, 5 eq), followed by acetic acid (4.8 μL, 0.084 mmol, 5 eq).After five minutes, sodium triacteoxyborohydride (17.9 mg, 0.084 mmol, 5eq) was added. After 2.5 h, another portion of sodiumtriacetoxyborohydride (20 mg, 0.094 mmol, 5.5 eq) was added. After anadditional 1.75 h, the reaction solution was diluted with aqueous sodiumbicarbonate solution (2 mL) and stirred 15 min, then was diluted furtherwith aqueous sodium bicarbonate solution (10 mL) and extracted withEtOAc (2×25 mL). The combined organic layers were dried over Na₂SO₄,were filtered, and were concentrated under reduced pressure. Theresulting crude oil was used for the following reaction without furtherpurification.

A solution of the above crude oil (0.017 mmol, 1 eq),tetrakis(triphenylphosphine)-palladium (3.1 mg, 0.0027 mmol, 0.1 eq) anddimethylbarbituric acid (20.0 mg, 0.128 mmol, 5 eq) in dichloromethane(1 mL) was degassed with bubbling nitrogen gas for two minutes and thenstirred at ambient temperature for 24 h. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution (15 mL) andextracted with EtOAc (2×25 mL). The organic layer was dried over Na₂SO₄,was filtered, and was concentrated under reduced pressure. Purificationof the resulting residue via flash column chromatography (Biotage, 10 gsilica gel column, 17% to 70% EtOAc in hexanes gradient) provided thedesired compound S19-6-9-3-A (11.9 mg, 49%): ¹H NMR (diastereomer A, 400MHz, CDCl₃: rotamers); MS (ESI) m/z 880.47 (M+H).

S19-6-9-3-B (diastereomer B) was prepared similarly to compoundS19-6-9-3-A from S19-6-6-2-B (diastereomer B) via reductive alkylationand deallylation as above: ¹H NMR (diastereomer B, 400 MHz, CDCl₃:rotamers); MS (ESI) m/z 880.47 (M+H).

S19-7-3-A (diastereomer A) was prepared similarly to compound S19-7-1-Bfrom S19-6-9-3-A (diastereomer A) via treatment with dimethylsulfide inmethanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ6.98 (d, J=5.5 Hz, 1H),4.87-4.76 (m, 2H), 3.81 (s, 1H), 3.50-3.39 (m, 2H), 3.19 (dd, J=15.3,4.3 Hz, 1H), 3.09-2.96 (m, 1H), 2.91 (s, 3H), 2.81 (d, J=12.2 Hz, 1H),2.55-2.45 (m, 1H), 2.38-2.09 (m, 6H), 1.63-1.51 (m, 1H); MS (ESI) m/z488.26 (M+H).

S19-7-3-B (diastereomer B) was prepared similarly to compound S19-7-1-Bfrom S19-6-9-3-B (diastereomer B) via treatment with dimethylsulfide inmethanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ6.99 (d, J=6.1 Hz, 1H),4.86-4.77 (m, 2H), 3.81 (s, 1H), 3.50-3.40 (m, 2H), 3.19 (dd, J=15.3,4.3 Hz, 1H), 3.09-2.97 (m, 1H), 2.91 (s, 3H), 2.81 (d, J=12.9 Hz, 1H),2.54-2.45 (m, 1H), 2.38-2.11 (m, 6H), 1.63-1.51 (m, 1H); MS (ESI) m/z488.25 (M+H).

S19-7-4-A (diastereomer A) was prepared similarly to compound S19-7-1-Bfrom S19-6-9-2-A (diastereomer A) via treatment with dimethylsulfide inmethanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ6.99 (d, J=6.1 Hz, 1H),4.23, 4.14 (s, s, 1H), 3.55-3.42 (m, 2H), 3.39-3.31 (m, 1H), 3.25-3.16(m, 1H), 3.14-2.90 (m, 6H), 2.56-2.47 (m, 1H), 2.39-2.10 (m, 6H),1.72-1.58 (m, 1H), 1.45-1.34 (m, 3H); MS (ESI) m/z 516.29 (M+H).

S19-7-4-B (diastereomer B) was prepared similarly to compound S19-7-1-Bfrom S19-6-9-2-B (diastereomer B) via treatment with dimethylsulfide inmethanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ6.99 (d, J=6.1 Hz, 1H),4.21, 4.12 (s, s, 1H), 3.54-3.40 (m, 3H), 3.25-3.15 (m, 1H), 3.14-2.86(m, 6H), 2.56-2.42 (m, 1H), 2.42-2.09 (m, 6H), 1.72-1.56 (m, 1H),1.45-1.34 (m, 3H); MS (ESI) m/z 516.30 (M+H).

Lithium diisopropylamide (2.1 eq) was prepared at −40° C. fromn-butyllithium (1.6M solution in hexane, 324 μL, 0.519 mmol) anddiisopropylamine (77 μL, 0.543 mmol) in THF (4 mL). The solution wascooled to −78° C. and TMEDA (81.5 μL, 0.543 mmol, 2.2 eq) was added,followed by drop wise addition of compound S19-5-2 (210 mg, 0.500 mmol,2.0 eq) in THF (900 μL) with a 200 μL THF rinse forward, maintaining theinternal temp below −70° C. The solution became red-orange in color.After 30 min at this temperature, a solution of diallylenone S1-9-2 (132mg, 0.247 mmol, 1 eq) in THF (900 μL) was added drop wise via syringewith a 200 μL THF rinse forward, maintaining the internal temperaturebelow −70° C. Lithium hexamethyldisilazane (1M in THF, 247 μL, 0.247mmol, 1 eq). After complete addition, the reaction mixture was allowedto warm to −10° C. over 1 h. Excess base was quenched at −10° C. by theaddition of saturated aqueous NH₄Cl solution (5 mL) and the mixture wasallowed to warm to ambient temperature. The reaction mixture was dilutedwith saturated aqueous NH₄Cl solution (15 mL) and water (3 mL), andextracted with EtOAc (2×25 mL). Combined organic extracts were driedover Na₂SO₄, were filtered, and were concentrated under reducedpressure. The material was purified via flash column chromatography(Biotage, 50 g silica gel column, 8% to 80% EtOAc in hexanes gradient),which produced a mixture of product S19-6-2 and remaining S19-5-2.Further purification on a Waters Autopurification system equipped with aSunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;gradient: 10→100% B; mass-directed fraction collection], provideddesired compound S19-6-2 (103 mg, 49%): ¹H NMR (400 MHz, CDCl₃) δ 16.13(s, 1H), 7.56-7.45 (4H), 7.44-7.29 (m, 5H), 7.28-7.23 (m, 1H), 7.19-7.09(m, 1H), 5.90-5.71 (m, 2H), 5.36 (s, 2H), 5.33-5.03 (m, 8H), 3.57-3.44(m, 1H), 3.40-3.27 (m, 2H), 3.27-3.10 (m, 4H), 3.07-2.95 (m, 1H),2.72-2.55 (m, 1H), 2.54-2.04 (m, 8H), 2.01-1.79 (m, 1H), 1.75-1.57 (m,1H), 1.02-0.75 (m, 9H), 0.27 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 860.59(M+H).

S19-6-5-1 and S19-6-5-2 were prepared similarly to S19-6-6-1 andS19-6-6-2 from S19-6-2 (103 mg, 0.121 mmol) via treatment with catalyticbis(dibenzylideneacetone)palladium(0) and1,4-bis(diphenylphosphinebutane) in the presence of 2-mercaptobenzoicacid. S19-6-5-2 (monoallyl, mixture of diastereomers, 34.8 mg, 35%): MS(ESI) m/z 820.53 (M+H). S19-6-5-1 (amino, mixture of diastereomers, 27.1mg, 29%): MS (ESI) m/z 780.47 (M+H). Unreacted starting material wasalso recovered (S19-6-2, 21.6 mg, 21%).

S19-7-5-A (diastereomer A) and S19-7-5-B (diastereomer B) were preparedsimilarly to compound S19-7-1-B from S19-6-5-1 (diastereomeric mixture)via treatment with dimethylsulfide in methanesulfonic acid.Diastereomers were separated on purification. S19-7-5-A (diastereomerA): ¹H NMR (400 MHz, CD₃OD) δ7.07 (d, J=5.5 Hz, 1H), 4.72-4.66 (m, 1H),3.91-3.80 (m, 2H), 3.41-3.30 (m, 1H), 3.21 (dd, J=15.9, 3.7 Hz, 1H),3.07-2.96 (m, 1H), 2.87 (s, 3H), 2.65 (d, J=12.8 Hz, 1H), 2.61-2.51 (m,1H), 2.42-2.20 (m, 5H), 1.66-1.54 (m, 1H); MS (ESI) m/z 488.22 (M+H).S19-7-5-B (diastereomer B): ¹H NMR (400 MHz, CD₃OD) δ ¹H NMR (400 MHz,CD₃OD) δ7.07 (d, J=6.1 Hz, 1H), 4.76-4.67 (m, 1H), 3.91-3.79 (m, 2H),3.41-3.30 (m, 1H), 3.20 (dd, J=15.3, 4.9 Hz, 1H), 3.07-2.96 (m, 1H),2.87 (s, 3H), 2.65 (d, J=12.8 Hz, 1H), 2.61-2.51 (m, 1H), 2.42-2.20 (m,5H), 1.66-1.54 (m, 1H); MS (ESI) m/z 488.22 (M+H).

S19-6-8-1 (diastereomeric mixture) was prepared similarly to compoundS19-6-9-1 from S19-6-5-1 (diastereomeric mixture) via treatment withacetaldehyde and sodium triacetoxyborohydride. S19-6-8-1 (diastereomericmixture): MS (ESI) m/z 808.51 (M+H).

S19-7-6 (diastereomeric mixture) was prepared similarly to compoundS19-7-1-B from S19-6-8-1 (diastereomeric mixture) via treatment withdimethylsulfide in methanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ7.10(d, J=5.5 Hz, 1H), 4.78-4.68 (m, 1H), 3.92-3.81 (m, 2H), 3.48-3.32 (m,3H), 3.25-3.14 (m, 1H), 3.10-2.98 (m, 1H), 2.92-2.82 (m, 4H), 2.62-51(m, 1H), 2.40-2.22 (m, 5H), 1.65-1.50 (m, 1H), 1.36 (t, J=7.3 Hz, 3H);MS (ESI) m/z 516.26 (M+H).

S19-6-8-2 was prepared from S19-6-5-2 similarly to compound S19-6-9-3via reductive alkylation with aqueous formaldehyde withtriacetoxyborohydride followed by allyl deprotection withtetrakis(triphenylphosphine)palladium and dimethylbarbituric acid.S19-6-8-2 (diastereomeric mixture): MS (ESI) m/z 794.53 (M+H).

S19-7-7-A (diastereomer A) and S19-7-7-B (diastereomer B) were preparedsimilarly to compound S19-7-1-B from S19-6-8-2 (diastereomeric mixture)via treatment with dimethylsulfide in methanesulfonic acid.Diastereomers were separated on purification. S19-7-7-A (diastereomerA): ¹H NMR (400 MHz, CD₃OD) δ7.07 (d, J=5.5 Hz, 1H), 4.71 (t, J=7.9 Hz,1H), 3.89-3.77 (m, 2H), 3.40-3.35 (m, 1H), 3.20 (dd, J=15.2, 4.9 Hz,1H), 3.10-2.97 (m, 1H), 2.91 (s, 3H), 2.87 (s, 3H), 2.80 (d, J=12.2 Hz,1H), 2.62-2.50 (m, 1H), 2.42-2.16 (m, 5H), 1.64-1.51 (m, 1H); MS (ESI)m/z 502.30 (M+H). S19-7-7-B (diastereomer B): ¹H NMR (400 MHz, CD₃OD)δ7.07 (d, J=5.5 Hz, 1H), 4.74-4.64 (m, 1H), 3.89-3.77 (m, 2H), 3.40-3.35(m, 1H), 3.18 (dd, J=15.2, 4.9 Hz, 1H), 3.09-2.97 (m, 1H), 2.90 (s, 3H),2.86 (s, 3H), 2.80 (d, J=12.2 Hz, 1H), 2.62-2.50 (m, 1H), 2.40-2.17 (m,5H), 1.64-1.52 (m, 1H); MS (ESI) m/z 502.30 (M+H).

The following compounds were prepared according to Scheme 20.

To a solution of S20-1 (single enantiomer, 257 mg, 0.528 mmol, 1 eq,prepared from S4-6 with similar procedures used for the preparation ofS4-11 without the bromination and trifluoromethylation steps) indichloroethane (5 mL) was added aqueous formaldehyde (37%, 196 μL, 2.64mmol, 5 eq), followed by acetic acid (150 μL, 2.64 mmol, 5 eq). After 25min, sodium triacteoxyborohydride (555 mg, 2.64 mmol, 5 eq) was added.After 55 min, the reaction solution was diluted with aqueous sodiumbicarbonate solution (4 mL) and stirred 20 min, then was diluted furtherwith aqueous sodium bicarbonate solution (15 mL), water (5 mL) andextracted with EtOAc (2×30 mL). The combined organic layers were driedover Na₂SO₄, were filtered, and were concentrated under reduced pressureto produce a crude oil.

The material was dissolved in dioxane:MeOH (1:1, 2 mL), and palladium oncarbon (Degussa, 10 wt %, 55 mg) was added. An atmosphere of hydrogenwas introduced and the reaction mixture was stirred for 5.5 h. Anotherportion of palladium catalyst (40 mg) was added, followed byreintroduction of hydrogen atmosphere. After an additional hour, thereaction mixture was filtered through a small Celite pad and thefiltrate was concentrated under reduced pressure.

To a solution of the above crude oil in dichloromethane (2.6 mL) wasadded di-tert-butyl dicarbonate (166 mg, 0.761 mmol, 1.5 eq) anddimethylaminopyridine (3 mg, 0.024 mmol, 0.05 eq) and the reactionmixture was stirred at ambient temperature. After 90 min, the mixturewas diluted with saturated aqueous ammonium chloride (20 mL), water (1mL) and extracted with EtOAc (2×25 mL). The combined organic layers weredried over Na₂SO₄, were filtered, and were concentrated under reducedpressure. Purification of the resulting residue via flash columnchromatography (Biotage, 25 g silica gel column, 2% to 50% EtOAc inhexanes gradient) provided the desired compound S20-2 (166 mg, 77%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.38 (m, 2H), 7.28-7.21 (m,3H), 7.19-7.16 (m, 1H), 7.09 (s, 1H), 3.29-3.21 (m, 1H), 3.13-3.04 (m,1H), 2.51 (s, 3H), 2.36-3.28 (m, 1H), 2.23-2.04 (m, 4H), 2.02-1.88 (m,1H), 1.86-1.68 (m, 2H), 1.42 (s, 9H); MS (ESI) m/z 410.27 (M−H).

Lithium diisopropylamide (2.5 eq) was prepared at −40° C. fromn-butyllithium (1.6M solution in hexane, 484 μL, 0.775 mmol) anddiisopropylamine (114 μL, 8.06 mmol) in THF (5 mL). The solution wascooled to −78° C. and TMEDA (120 μL, 0.806 mmol, 2.6 eq) was added,followed by drop wise addition of compound S20-2 (166 mg, 0.403 mmol,1.3 eq) in THF (1 mL) with a 500 μL THF rinse forward, maintaining theinternal temperature below −70° C. The solution became a deep red color.After 30 min at this temperature, the solution was cooled to −100° C. Asolution of diallylenone S1-9-2 (165 mg, 0.308 mmol, 1 eq) in THF (1 mL)was added drop wise via syringe with a 500 μL THF rinse forward,maintaining the internal temperature below −90° C. After completeaddition, the reaction mixture was allowed to warm slowly in the bath.When the solution reached −78° C., lithium hexamethyldisilazane (1M inhexanes, 310 μL, 1 eq) was added. After 70 min, excess base was quenchedat −10° C. by the addition of a saturated aqueous NH₄Cl solution (3 mL)and the mixture was warmed to ambient temperature. The reaction mixturewas diluted with saturated aqueous NH₄Cl solution (15 mL) and water (2mL) and was extracted with EtOAc (2×25 mL). Combined organic extractswere dried over Na₂SO₄, were filtered, and were concentrated underreduced pressure. Purification of the resulting residue via flash columnchromatography (Biotage, 25 g silica gel column, 7% to 60% EtOAc inhexanes gradient) provided the desired compound S20-3-1 (singlediastereomer, 203.8 mg, 70%) as a yellow foam (>90% purity): ¹H NMR (400MHz, CDCl₃) δ 15.61 (s, 1H), 7.40-7.34 (m, 2H), 7.30-7.19 (m, 3H),7.06-6.98 (m, 1H), 6.90 (s, 1H), 5.74-5.61 (m, 2H), 5.24 (s, 2H), 5.12(d, J=17.1 Hz, 2H), 5.00 (d, J=9.8 Hz, 2H), 3.26-3.05 (m, 4H), 3.05-2.79(m, 3H), 2.76-2.68 (m, 1H), 2.41-2.26 (m, 2H), 2.25-2.02 (m, 5H),2.01-1.93 (m, 1H), 1.90-1.54 (m, 3H), 1.53-1.43 (m, 1H), 1.42 (s, 9H),0.71 (s, 9H), 0.14 (s, 3H), 0.00 (s, 3H); MS (ESI) m/z 850.53 (M−H).

A solution of S20-3-1 (103 mg, 0.121 mmol, 1 eq),tetrakis(triphenylphosphine)-palladium (7.0 mg, 0.0.0061 mmol, 0.05 eq)and dimethylbarbituric acid (95.5 mg, 0.612 mmol, 5 eq) under nitrogenwas dissolved in dichloromethane (1.5 mL) and stirred at ambienttemperature. After 22 h, additional solvent (500 μL) and Pd catalyst (8mg, 0.007 mmol, 0.06 eq) were added. After an additional 2.5 h, thereaction mixture was diluted with saturated aqueous sodium bicarbonatesolution (15 mL) and water (2 mL) and extracted with EtOAc (2×35 mL).The organic layer was dried over Na₂SO₄, was filtered, and wasconcentrated under reduced pressure. Purification of the resultingresidue via flash column chromatography (Biotage, 25 g silica gelcolumn, 40% to 100% EtOAc in hexanes, then 10% MeOH in dichloromethanegradient) provided the desired compound S20-3-2 (single diastereomer,80.6 mg, 86%). ¹H NMR (rotamers, 400 MHz, CDCl₃) δ 16.33 (s, 1H),7.72-7.63 (m, 2H), 7.59-7.43 (m, 2H), 7.42-7.31 (m, 1H), 7.13 (s, 1H),7.04 (s, 1H), 5.44-5.33 (m, 2H), 3.97 (brs, 1H), 3.28-3.21 (m, 1H),3.15-3.05 (m, 1H), 3.04-2.89 (m, 1H), 2.82-2.72 (m, 1H), 2.68-2.56 (m,2H), 2.38-2.27 (m, 1H), 2.26-2.08 (m, 6H), 2.01-1.90 (m, 1H), 1.89-1.67(m, 2H), 1.65-1.51 (m, 9H), 0.91-0.72 (m, 9H), 0.26-0.08 (m, 6H); MS(ESI) m/z 772.47 (M+H).

To a solution of S20-3-1 (100 mg, 0.117 mmol, 1 eq) and2-mercaptobenzoic acid (23 mg, 0.149 mmol, 1.2 eq) in THF (1 mL) underN₂ was added 500 μL of a dry, air-free, prepared solution ofbis(dibenzylideneacetone)palladium(0) and1,4-bis(diphenylphosphinebutane) in THF (0.02M in catalyst/ligand, 1 mL)drop wise via syringe. After 19 h, another portion of palladium catalyst(6.7 mg, 0.012 mmol, 0.1 eq), ligand (6 mg, 0.014 mmol, 1.2 eq) and2-mercaptobenzoic acid (25 mg, 0.16 mmol, 1.4 eq) was added. After anadditional 24 h, the reaction mixture was diluted with saturated aqueoussodium bicarbonate solution (20 mL) and water (2 mL) and extracted withEtOAc (2×25 mL). The combined organic layers were dried over Na₂SO₄,were filtered, and were concentrated under reduced pressure.Purification of the resulting residue via flash column chromatography(Biotage, 25 g silica gel column, 5% to 80% EtOAc in hexanes gradient)provided the monoallyl compound S20-3-3 (25 mg, 26%), and recovereddiallyl S20-3-1 (52.7 mg, 53%). Monoallyl S20-3-3: ¹H NMR (400 MHz,CDCl₃, single diastereomer, rotamers) δ 16.30 (s, 1H), 7.43-7.37 (m,2H), 7.33-7.23 (m, 3H), 7.02 (s, 1H), 6.94 (s, 1H), 5.86-5.74 (m, 1H),5.33 (d, J=12.2 Hz, 1H), 5.29 (d, J=12.2 Hz, 1H), 5.21 (d, J=17.7 Hz,1H), 5.08 (d, J=9.8 Hz, 1H), 3.68 (s, 1H), 3.48 (dd, J=13.4, 6.1 Hz,1H), 3.35 (dd, J=13.4, 6.1 Hz, 1H), 3.18-3.11 (m, 1H), 3.03-2.95 (m,1H), 2.90-2.75 (m, 1H), 2.69-2.60 (m, 2H), 2.52-2.41 (m, 1H), 2.30-2.05(m, 5H), 2.00-1.57 (m, 4H), 1.56-1.36 (m, 10H), 0.66 (s, 9H), 0.10 (s,3H), 0.00 (s, 3H); MS (ESI) m/z 812.55 (M+H).

S20-4-1 (single diastereomer) was prepared similarly to compoundS19-7-1-B from S20-3-2 (single diastereomer) via treatment withdimethylsulfide in methanesulfonic acid: ¹H NMR (400 MHz, CD₃OD,methanesulfonic acid salt) δ 6.98 (s, 1H), 6.92 (s, 1H), 4.37-4.27 (m,1H), 3.90-3.78 (m, 2H), 3.07-2.97 (m, 1H), 2.93 (dd, J=15.2, 4.3 Hz,1H), 2.80 (s, 3H), 2.66-2.47 (m, 3H), 2.34-2.16 (m, 4H), 2.02 (s, 3H,MeSO₃H), 1.62-1.50 (m, 1H); MS (ESI) m/z 470.21 (M+H).

S20-3-4-1 (single diastereomer) was prepared similarly to compoundS19-6-9-1 from S20-3-2 (single diastereomer) via treatment withacetaldehyde and sodium triacetoxyborohydride. ¹H NMR (400 MHz, CDCl₃,single diastereomer) δ 16.26 (s, 1H), 7.41-7.34 (m, 3H), 7.31-7.21 (m,3H), 6.94 (s, 1H), 5.33-5.24 (m, 2H), 3.66 (d, J=2.4 Hz, 1H), 3.02-2.89(m, 1H), 2.88-2.77 (m, 1H), 2.73-2.58 (m, 2H), 2.53-2.41 (m, 1H),2.30-2.05 (m, 3H), 2.00-1.92 (m, 2H), 1.56-1.37 (m, 11H), 1.34-1.23 (m,1H), 1.05 (t, J=7.3 Hz, 3H), 0.67 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H);MS (ESI) m/z 800.51 (M+H).

S20-4-2 (single diastereomer) was prepared similarly to compoundS19-7-1-B from S20-3-4-1 (single diastereomer) via treatment withdimethylsulfide in methanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ 6.99(s, 1H), 6.96 (s, 1H), 4.36-4.29 (m, 1H), 3.89-3.80 (m, 2H), 3.48-3.33(m, 1H), 3.08-2.98 (m, 1H), 2.92 (dd, J=15.2, 4.3 Hz, 1H), 2.84-2.78 (m,5H), 2.64-2.50 (m, 2H), 2.34-2.17 (m, 5H), 1.59-1.46 (m, 1H), 1.35 (t,J=6.7 Hz, 3H); MS (ESI) m/z 498.27 (M+H).

S20-4-3 (single diastereomer) was prepared similarly to compound S19-7-4from S20-3-4-1 (single diastereomer) via reductive alkylation withaqueous formaldehyde followed by deprotection via treatment withdimethylsulfide in methanesulfonic acid: ¹H NMR (400 MHz, CD₃OD) δ 7.00(s, 1H), 6.97 (s, 1H), 4.38-4.29 (m, 1H), 4.22, 4.12 (s, s, 1H),3.89-3.80 (m, 1H), 3.53-3.42 (m, 1H), 3.15-3.03 (m, 1H), 3.02-2.89 (m,4H), 2.81 (s, 3H), 2.65-2.47 (m, 2H), 2.34-2.15 (m, 4H), 1.66-1.54 (m,1H), 1.45-1.33 (m, 3H); MS (ESI) m/z 512.30 (M+H).

S20-4-4 (single diastereomer) was prepared similarly to compound S19-7-3from S20-3-3 (single diastereomer) via reductive alkylation with aqueousformaldehyde followed by allyl deprotection and treatment withdimethylsulfide in methanesulfonic acid. ¹H NMR (400 MHz, CD₃OD) δ 6.99(s, 1H), 6.96 (s, 1H), 4.36-4.29 (m, 1H), 3.89-3.78 (m, 2H), 3.09-2.98(m, 1H), 2.96-2.87 (m, 4H), 2.83-2.76 (m, 4H), 2.64-2.47 (m, 2H),2.33-2.14 (m, 4H), 1.60-1.48 (m, 1H); MS (ESI) m/z 484.25 (M+H).

The following compounds were prepared according to Scheme 21.

Lithium diisopropylamide (1.6 eq) was prepared at −40° C. fromn-butyllithium (1.6M solution in hexane, 382 μL, 0.611 mmol) anddiisopropylamine (91.7 μL, 0.649 mmol) in THF (5 mL). The solution wascooled to −78° C. and TMEDA (97.3 μL, 0.649 mmol, 1.7 eq) was added,followed by drop wise addition of compound S21-1 (346.8 mg, 0.561 mmol,1.5 eq, prepared according to literature procedures includingWO2011025982) in THF (1 mL) with a 500 μL THF rinse forward, maintainingthe internal temperature below −70° C. The solution became a deep redcolor. After 30 min at this temperature, the solution was cooled to−100° C. A solution of diallylenone S1-9-2 (204 mg, 0.382 mmol, 1 eq) inTHF (1 mL) was added drop wise via syringe with a 400 μL THF rinseforward, maintaining the internal temperature below −90° C. Aftercomplete addition, the reaction mixture was allowed to warm slowly inthe bath. When the solution reached −78° C., lithiumhexamethyldisilazane (1M in hexanes, 382 μL, 1 eq) was added. After 90min, excess base was quenched at −10° C. by the addition of a saturatedaqueous NH₄Cl solution (3 mL) and the mixture was warmed to ambienttemperature. The reaction mixture was diluted with saturated aqueousNH₄Cl solution (20 mL) and water (2 mL) and was extracted with EtOAc(2×25 mL). Combined organic extracts were dried over Na₂SO₄, werefiltered, and were concentrated under reduced pressure. Purification ofthe resulting residue on a Waters Autopurification system equipped witha Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;gradient: 90→100% B; mass-directed fraction collection], provideddesired compound S21-2 (218 mg, 54%, >85% desired, impurity is mono-Bocprotected aniline): MS (ESI) m/z 1058.03 (M+H).

To a solution of S21-2 (215 mg, 0.204 mmol, 1 eq) in dioxane (1.5 mL)was added a 4N solution of HCl in dioxane (1.5 mL). After 3.5 h, thereaction was cooled to 0° C. and a saturated sodium bicarbonate solution(6 mL) was added dropwise, followed by EtOAc (5 mL). After 10 min, theheterogeneous solution was warmed to ambient temperature and furtherdiluted with saturated sodium bicarbonate solution (15 mL) and extractedwith EtOAc (2×25 mL). The combined organic extracts were dried overNa₂SO₄, were filtered, and were concentrated under reduced pressure toyield intermediate S21-3, which was used without further purification:MS (ESI) m/z 858.44 (M+H).

To a solution of S21-3 (0.101 mmol, 1 eq) in THF (2 mL) was addedbromoacetylbromide (11.5 μL, 0.132 mmol, 1.3 eq). After 19 h, a solutionof dimethylamine in ethanol (5.6M, 150 μL, 0.84 mmol, 8.4 eq) was added.After 3 h, the reaction was diluted with EtOAc (20 mL) and washed with asaturated aqueous sodium bicarbonate solution (15 mL). The aqueous layerwas extracted with EtOAc (20 mL), and the combined organic extracts weredried over Na₂SO₄, were filtered, and were concentrated under reducedpressure. Purification of the resulting residue via flash columnchromatography (Biotage, 25 g silica gel column, 5% to 40% EtOAc inhexanes gradient) provided the desired product S21-4-1-1 (43.6 mg, 46%):¹H NMR (400 MHz, CDCl₃, rotamers) δ 15.82, 15.72 (s, s, 1H), 9.87 (brs,1H), 8.65 (brs, 1H), 7.54-7.45 (m, 2H), 7.44-7.28 (m, 9H), 5.87-5.69 (m,2H), 5.38-5.34 (m, 2H), 5.22 (d, J=17.1 Hz, 2H), 5.17-5.06 (m, 2H),5.03-4.91 (m, 2H), 4.82 (d, J=10.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.37-3.25(m, 1H), 3.25-3.08 (m, 4H), 3.07-2.91 (m, 3H), 2.71-2.60 (m, 1H),2.57-2.10 (m, 10H), 0.88-0.77 (m, 9H), 0.29-0.21 (m, 3H), 0.13-0.09 (s,3H); MS (ESI) m/z 941.52 (M−H).

S21-4-2-1 was prepared similarly to S19-6-6-2 via deallylation ofS21-4-1-1 with bis(dibenzylideneacetone)palladium(0) and1,4-bis(diphenylphosphinebutane) in the presence of 2-mercaptobenzoicacid: MS (ESI) m/z 903.48 (M+H).

S21-5-1 was prepared similarly to compound S19-7-3 from S21-4-2-1 viareductive alkylation with aqueous formaldehyde followed by allyldeprotection and treatment with dimethylsulfide in methanesulfonic acid:¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 4.24 (s, 2H), 3.80 (s, 1H),3.07-2.92 (m, 8H), 2.91 (s, 3H), 2.82-2.75 (m, 1H), 2.37-2.27 (m, 1H),2.24-2.15 (m, 1H), 1.66-1.51 (m, 1H); MS (ESI) m/z 585.28 (M+H).

S21-4-1-2 was prepared similarly to S21-4-1-1 via treatment withbromoacetylbromide followed by addition of n-butylamine. Rotamers wereobserved by ¹HNMR (CDCl₃). MS (ESI) m/z 972.13 (M+H).

To a solution of S21-4-1-2 (35.4 mg, 0.036 mmol, 1 eq) indichloromethane (800 μL) was added di-tert-butyl dicarbonate (10 mg,0.046 mmol, 1.2 eq) and dimethylaminopyridine (2 mg, 0.016 mmol, 0.4 eq)and the reaction mixture was stirred at ambient temperature. After 22 h,the mixture was diluted with saturated aqueous ammonium chloride (10mL), water (1 mL) and extracted with EtOAc (2×25 mL). The combinedorganic layers were dried over Na₂SO₄, were filtered, and wereconcentrated under reduced pressure. A crude ¹HNMR spectrum of theresulting residue indicated incomplete reaction and it was resubmittedto the above reaction conditions and work up. Purification of theresulting residue via flash column chromatography (Biotage, 10 g silicagel column, 1% to 35% EtOAc in hexanes gradient) provided compoundS21-4-1-3 (15 mg, 39%). Rotamers observed in ¹HNMR (400 MHz, CDCl₃). MS(ESI) m/z 997.53 (M+H).

Aqueous HF (48%, 150 μL) was added to a solution of S21-4-1-3 (15 mg,0.013 mmol) in dioxane (500 μL) in a plastic vial. After 23 h thereaction mixture was poured into a solution of K₂HPO₄ (1.8 g) in water(10 mL). The mixture was extracted with EtOAc (2×25 mL). The combinedEtOAc extracts were dried over Na₂SO₄, were filtered, and were andconcentrated under reduced pressure. The material was dissolved in MeOH(1 mL) and aqueous HCl (1M, 50 μL), and palladium on carbon (Degussa, 10wt %, 10 mg) was added. An atmosphere of hydrogen was introduced and thereaction mixture was stirred for 2 h. The reaction mixture was filteredthrough a small Celite pad and the filtrate was concentrated underreduced pressure. The material was purified on a Waters Autopurificationsystem equipped with a Phenomenex Polymerx 10 RP 100A column [10 μm,30×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl in water;Solvent B: CH₃CN; gradient: 5→60% B; mass-directed fraction collection].Fractions with the desired MW were collected and freeze-dried to yieldcompound S21-5-2 (monopropylamino, 1.78 mg, 18%) and compound S21-5-3(dipropylamino, 0.83 mg, 8%) as yellow solids. S21-5-2: ¹H NMR (400 MHz,CD₃OD, monopropylamino,) δ 7.56 (s, 1H), 4.17 (s, 2H), 3.87 (s, 1H),3.52-3.40 (m, 2H), 3.28-3.14 (m, 4H), 3.08-2.97 (m, 1H), 2.83 (d, J=12.8Hz, 1H), 2.46-2.35 (m, 1H), 2.25-2.16 (m, 1H), 1.82-1.70 (m, 2H),1.68-1.56 (m, 3H), 1.46-1.34 (m, 2H), 1.03 (t, J=7.32 Hz, 3H), 0.98 (t,J=7.32 Hz, 3H); MS (ESI) m/z 667.30 (M+H). S21-5-3: ¹H NMR (400 MHz,CD₃OD, dipropylamino,) δ 7.57 (s, 1H), 4.23 (s, 1H), 4.19 (s, 2H),3.56-3.40 (m, 4H), 3.23-3.03 (m, 1H), 2.97-2.90 (m, 1H), 2.47-2.37 (m,1H), 2.25-2.17 (m, 1H), 1.92-1.79 (m, 5H), 1.70-1.58 (m, 4H), 1.48 (s,1H), 1.46-1.35 (m, 2H), 1.08-0.94 (m, 9H); MS (ESI) m/z 709.34 (M+H).

To a solution of S21-4-1-2 (32.4 mg, 0.033 mmol, 1 eq) indichloromethane (1.5 mL) and methanol (600 μL) was added di-tert-butyldicarbonate (8 mg, 0.037 mmol, 1.1 eq) and the reaction mixture wasstirred at ambient temperature. After 4.5 h, the mixture was dilutedwith saturated aqueous ammonium chloride (10 mL), water (3 mL) andextracted with EtOAc (2×25 mL). The combined organic layers were driedover Na₂SO₄, were filtered, and were concentrated under reducedpressure. Combined with a second reaction (0.011 mmol of S21-4-1-2) andpurified via flash column chromatography (Biotage, 10 g silica gelcolumn, 1% to 35% EtOAc in hexanes gradient) to provide compoundS21-4-1-4 (30.3 mg, 64%). Rotamers observed in ¹HNMR (400 MHz, CDCl₃).MS (ESI) m/z 1071.66 (M+H).

S21-4-2-2 was prepared similarly to S20-3-2 from S21-4-1-4 viadeallylation with tetrakis(triphenylphosphine)palladium anddimethylbarbituric acid. ¹HNMR (400 MHz, CDCl₃) indicates rotamers. MS(ESI) m/z 991.58 (M+H).

S21-5-4 was prepared similarly to S19-7-4 from S21-4-2-2 via successivereductive alkylation with acetaldehyde and formaldehyde, then globaldeprotection via successive aqueous HF treatment and reduction overpalladium on carbon: ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 4.28-4.10(m, 1H), 4.09 (s, 2H), 3.58-3.30 (m, 2H), 3.22-2.87 (m, 8H), 2.37-2.17(m, 2H), 1.78-1.59 (m, 3H), 1.53-1.32 (m, 5H), 1.01 (t, J=7.3 Hz, 3H);MS (ESI) m/z 641.34 (M+H).

The compounds in Table 2A were synthesized according to Scheme 22 fromdimethylamino enone S22-2 and a properly substituted and protectedD-ring intermediate S22-1. A synthesis of enone S22-2 is described inU.S. Pat. No. 7,807,842 and Org. Lett., 2007, 9(18), 3523-3525, therelevant portions of which are incorporated herein by reference. S22-1was prepared by a procedure similar to that used to prepare S6-4.

TABLE 2A MS (ESI) Compound No. Compound Structure m/z (M + H) S22-4-1-A(diastereomer A) S22-4-1-B (diastereomer B)

527.36 (A) 527.34 (B) S22-4-2-A (diastereomer A) S22-4-2-B (diastereomerB)

553.42 (A) 553.33 (B) S22-4-3-A (diastereomer A) S22-4-3-B (diastereomerB)

513.31 (A) 513.33 (B) S22-4-4-A (diastereomer A) S22-4-2-B (diastereomerB)

555.1  S22-4-5-A (diastereomer A) S22-4-5-B (diastereomer B)

555.34 (A) 555.39 (B) S22-4-6-B (diastereomer B)

569.39 S22-4-7

555.2  S22-4-8-A (diastereomer A)

513.32 (A) S22-4-9-A (diastereomer A)

555.32 S22-4-10-A (diastereomer A) S22-4-10-B (diastereomer B)

555.2  S22-4-11-A (diastereomer A) S22-4-11-B (diastereomer B)

541.1  S22-4-12-A (diastereomer A) S22-4-12-B (diastereomer B)

569.1  S22-4-13-A (diastereomer A)

541.34 S22-4-14-A (diastereomer A)

569.35 S22-4-15-A (diastereomer A)

527.32 S22-4-16-A (diastereomer A)

553.37 S22-4-17-A

541.32 S22-4-18-A (diastereomer A)

567.36 S22-4-19-A (diastereomer A)

541.33 S22-4-20-A (diastereomer A)

555.35 S22-4-21-A (diastereomer A)

611.44 S22-4-22-A (diastereomer A)

607.38

The compounds in Table 2B were synthesized according to Scheme 23 fromdimethylamino enone S22-2 and a properly substituted and protectedD-ring intermediate S23-1. S23-1 was prepared by a procedure similar tothat used to prepare S5-8.

TABLE 2B MS (ESI) Compound No. Compound Structure m/z ( M + H) S23-4-1-A(diastereomer A) S23-4-1-B (diastereomer B)

539.15 S23-4-2-A (diastereomer A) S23-4-2-B (diastereomer B)

525.12 S23-4-3-B (diastereomer B)

553.17 S23-4-4-A (diastereomer A) S23-4-4-B (diastereomer B)

657.14 S23-4-5-B (diastereomer B)

553.11 S23-4-6-A (diastereomer A) S23-4-6-B (diastereomer B)

567.42 (A) 567.37 (B) S23-4-7-A (diastereomer A) S23-4-7-B (diastereomerB)

553.42 (A) 553.26 (B) S23-4-8-A (diastereomer A) S23-4-8-B (diastereomerB)

565.35

The compounds in Table 2C were synthesized according to Scheme 24 fromdimethylamino enone S22-2 and a properly substituted and protectedD-ring intermediate S24-1. S24-1 was prepared by a procedure similar tothat used to prepare S3-5.

TABLE 2C MS (ESI) Compound No. Compound Structure m/z (M + H) S24-4-1-A(diastereomer A) S24-4-1-B (diastereomer B)

543.07 S24-4-2-A (diastereomer A) S24-4-2-B (diastereomer B)

529.07 S24-4-3-A (diastereomer A) S24-4-3-B (diastereomer B)

557.15 S24-4-4-A (diastereomer A) S24-4-4-B (diastereomer B)

557.13 (A) 557.10 (B) S24-4-5-A (diastereomer A) S24-4-5-B (diastereomerB)

543.14 S24-4-6-A (diastereomer A) S24-4-6-B (diastereomer B)

585.26 S24-4-7-A (diastereomer A) S24-4-7-B (diastereomer B)

571.2  S24-4-8-A (diastereomer A) S24-4-8-B (diastereomer B)

585.18 S24-4-9-A S24-4-9-B S24-4-9-C S24-4-9-D (diastereomer A, B, C, D)

603.1  S24-4-10-A (diastereomer A) S24-4-10-B (diastereomer B)

573.1  S24-4-11-A (diastereomer A) S24-4-11-B (diastereomer B)

615.10  S24-4-12-A (diastereomer A) S24-4-12-B (diastereomer B)

600.1  S24-4-13-B (diastereomer B)

642.2+11 S24-4-14-A (diastereomer A) S24-4-14-B (diastereomer B)

636.2  S24-4-15

628.1 

The compounds in Table 2D were synthesized according to Scheme 25 fromdimethylamino enone S22-2 and a properly substituted and protectedD-ring intermediate S25-1. S25-1 was prepared by a procedure similar tothat used to prepare S12-6.

TABLE 2D MS (ESI) Compound No. Compound Structure m/z (M + H) S24-4-1-A(diastereomer A) S25-4-1-B (diastereomer B)

609.3 S25-4-2-A (diastereomer A) S25-4-2-B (diastereomer B)

623.1 (A) 623.4 (B) S25-4-3-A (diastereomer A) S25-4-3-B (diastereomerB)

635.1 S25-4-4-A (diastereomer A) S25-4-4-B (diastereomer B)

649.1 S25-4-5-A (diastereomer A) S25-4-5-B (diastereomer B)

651.1 S25-4-6

595.2

The compounds in Table 2E were synthesized according to Scheme 26 fromdimethylamino enone S22-2 and a properly substituted and protectedD-ring intermediate S26-1. S26-1 was prepared by a procedure similar tothat used to prepare S16-5-1.

TABLE 2E MS (ESI) Compound No. Compound Structure m/z (M + H) S26-4-1-A(diastereomer A) S26-4-1-B (diastereomer B)

531.25 S26-4-2-A (diastereomer A)

517.27 S26-4-3-A (diastereomer A)

545.30 S26-4-4-A (diastereomer A)

559.36 S26-4-5-A (diastereomer A)

567.19

The compounds in Table 2F were synthesized according to Scheme 27 fromdimethylamino enone S22-2 and a properly substituted and protectedD-ring intermediate S27-1. S27-1 was prepared by a procedure similar tothat used to prepare S15-8.

TABLE 2F MS (ESI) Compound No. Compound Structure m/z (M + H) S27-4-1-A(diastereomer A) S27-4-1-B (diastereomer B)

599.2 S27-4-2

601.1 S27-4-3

517.1 S27-4-4

545.1 S27-4-5

559.3 S27-4-6

573.1 S27-4-7

531.1 S27-4-8-B (diastereomer B)

545.3 S27-4-9-B (diastereomer B)

573.3 S27-4-10-B (diastereomer B)

573.3 S27-4-11-B (diastereomer B)

571.3 S27-4-12-B (diastereomer B)

559.3 S27-4-13-A (diastereomer A) S27-4-13-B (diastereomer B)

573.3 S27-4-14-B (diastereomer B)

570.3

Antibacterial Activity.

The antibacterial activities for the compounds of the invention werestudied according to the following protocols.

Minimum Inhibitory Concentration (MIC) Assay

MICs were determined according to the Clinical and Laboratory StandardsInstitute (CLSI) guidances (e.g., CLSI. Performance standards forantimicrobial susceptibility testing; nineteenth information supplement.CLSI document M100-S19, CLSI, 940 West Valley Road, Suite 1400, Wayne,Pa. 19087-1898, USA, 2009). Briefly, frozen bacterial strains werethawed and subcultured onto Mueller Hinton Broth (MHB) or otherappropriate media (Streptococcus requires blood and Haemophilus requireshemin and NAD). Following incubation overnight, the strains weresubcultured onto Mueller Hinton Agar and again incubated overnight.Colonies were observed for appropriate colony morphology and lack ofcontamination. Isolated colonies were selected to prepare a startinginoculum equivalent to a 0.5 McFarland standard. The starting inoculumwas diluted 1:125 (this is the working inoculum) using MHB for furtheruse. Test compounds were prepared by dilution in sterile water to afinal concentration of 5.128 mg/mL. Antibiotics (stored frozen, thawedand used within 3 hours of thawing) and compounds were further dilutedto the desired working concentrations.

The assays were run as follows. Fifty μL of MHB was added to wells 2-12of a 96-well plate. One hundred μL of appropriately diluted antibioticswas added to well 1. Fifty μL of antibiotics was removed from well 1 andadded to well 2 and the contents of well 2 mixed by pipetting up anddown five times. Fifty μL of the mixture in well 2 was removed and addedto well 3 and mixed as above. Serial dilutions were continued in thesame manner through well 12. Fifty μL was removed from well 12 so thatall contained 50 μL. Fifty μL of the working inoculum was then added toall test wells. A growth control well was prepared by adding 50 μL ofworking inoculum and 50 μL of MHB to an empty well. The plates were thenincubated at 37° C. overnight, removed from the incubator and each wellwas read on a plate reading mirror. The lowest concentration (MIC) oftest compound that inhibited the growth of the bacteria was recorded.

EXAMPLE

1 2 3 4 5 6 7 8 9 10 11 12 [Abt] 32 16 8 4 2 1 0.5 0.25 0.125 0.06 0.030.015 Growth − − − − − + + + + + + + [Abt] = antibiotic concentration inthe well in μg/ml Growth = bacterial growth (cloudiness) Interpretation:MIC = 2 μg/mL

Protocol for Determining Inoculum Concentration (Viable Count)

Fifty 50 μl of the inoculum was pipetted into well 1. Ninety μl ofsterile 0.9% NaCl was pipetted into wells 2-6 of a 96-well microtiterplate. Ten μL from was removed from well 1 and added it to well 2followed by mixing. Ten μL was removed from well two and mixed with thecontents of well 3 and so on creating serial dilutions through well 6.Ten μL was removed from each well and spotted onto an appropriate agarplate. The plate was placed into an incubator overnight. The colonies inspots that contain distinct colonies were counted. Viable count wascalculated by multiplying the number of colonies by the dilution factor.

Spot from Well 1 2 3 4 5 6 Dilution 10² 10³ 10⁴ 10⁵ 10⁶ 10⁷ Factor

Bacterial Strains

The following bacterial strains, listed below, were examined in minimuminhibitory concentration (MIC) assays.

STRAIN DESIG- ORGANISM NATION KEY PROPERTIES Staphylococcus aureus SA100ATCC 13709, MSSA, Smith strain Staphylococcus aureus SA101 ATCC 29213,CLSI quality control strain, MSSA Staphylococcus aureus SA191 HA-MRSA,tetracycline-resistant, lung infection model isolate Staphylococcusaureus SA161 HA-MRSA, tetracycline-resistant, tet(M) Staphylococcusaureus SA158 Tetracycline-resistant tet(K) aaaureusaureus StaphylococcusSE164 ATCC 12228, CLSI quality control epidermidis strain,tetracycline-resistant Enterococcus faecalis EF103 ATCC 29212, tet-I/R,control strain Enterococcus faecalis EF159 Tetracycline-resistant,tet(M) Enterococcus faecalis EF327 Wound isolate (US) tet(M)Enterococcus faecium EF404 Blood isolate (US) tet(M) Streptococcus SP106ATCC 49619, CLSI quality control pneumoniae strain Streptococcus SP160Tetracycline-resistant, tet(M) pneumoniae Streptococcus pyogenes SP3122009 clinical isolate, tet(M) Streptococcus pyogenes SP193 S. pyogenesfor efficacy models; tetS; sensitive to sulfonamides Haemophilusinfluenzae HI262 Tetracycline-resistant, ampicillin- resistant Moraxellacatarrhalis MC205 ATCC 8176, CLSI quality control strain Escherichiacoli EC107 ATCC 25922, CLSI quality control strain Escherichia coliEC155 Tetracycline-resistant, tet(A) Enterobacter cloacae EC108 ATCC13047, wt Enterobacter cloacae EC603 Urine isolate (Spain) Escherichiacoli EC878 MG1655 tolC::kan Klebsiella pneumoniae KP109 ATCC 13883, wtKlebsiella pneumoniae KP153 Tetracycline-resistant, tet(A), MDR, ESBL⁺Klebsiella pneumoniae KP457 2009 ESBL⁺, CTX-M, OXA Proteus mirabilisPM112 ATCC 35659 Proteus mirabilis PM385 Urine ESBL⁺ isolate Pseudomonasaeruginosa PA111 ATCC 27853, wt, control strain Pseudomonas aeruginosaPA169 Wt, parent of PA170-173 Pseudomonas aeruginosa PA173 PA170 ΔmexXMexXY-(missing a functional efflux pump) Pseudomonas aeruginosa PA555ATCC BAA-47, wild type strain PAO1 Pseudomonas aeruginosa PA556Multiple-Mex efflux pump knockout strain Pseudomonas aeruginosa PA6732009 urine isolate from catheter in male from East North Central USPseudomonas aeruginosa PA669 2009 clinical isolate from trachealaspirate Pseudomonas aeruginosa PA693 2009 isolate from corneal scrapingof female from Pacific US Pseudomonas aeruginosa PA1145 Strain used inmurine pneumonia model Acinetobacter baumannii AB110 ATCC 19606, wtAcinetobacter baumannii AB250 Cystic fibrosis isolate, MDRStenotrophomonas SM256 Cystic fibrosis isolate, MDR maltophiliaBurkholderia BC240 Cystic fibrosis isolate, MDR cenocepacia *MDR,multidrug-resistant; MRSA, methicillin-resistant S. aureus; MSSA,methicillin-sensitive S. aureus; HA-MRSA, hospital-associated MRSA;tet(K), major gram-positive tetracycline efflux mechanism; tet(M), majorgram-positive tetracycline ribosome-protection mechanism; ESBL⁺,extended spectrum β-lactamase

Results

Values of minimum inhibition concentration (MIC) for tested compounds ofthe invention are provided in Tables 3, 4, 5, 6, 7 and 8. In Tables 3-8,A=lower than or equal to lowest MIC among three control compounds;B=greater than lowest MIC among three control compounds, but lower thanor equal to the highest MIC among three control compounds; C=greaterthan MIC of all three control compounds; and ND=not determined. MICvalues for sancycline, minocycline and tigecycline are reported inμg/mL.

Mouse Pneumonia Study.

Organism: K. pneumoniae UNT023-1(KPC producing strain)Animals: Female CD-1 mice (22±2 g) (Harlan laboratories)Pretreatment: Cytoxan 150 mg/kg IP on day −4 for partial neutropenia(based on previous virulence studies).Infection procedure: Anesthetized the mice by IP injecting 0.15 mL of aketamine HCl (40 mg/kg b.w.)+xylazine (6 mg/kg b.w.) mixture.Intranasally (IN) inoculated anesthetized mice with 0.05 mL of thedesignated inoculum (final infective dose of approximately 6-7 log₁₀CFU/mouse). For IN inoculation, placed drops onto the external nares andwaited for inhalation. After inoculation, placed each mouse back intoits cage and monitored for recovery.Treatment: Dosing was initiated at 2 hours post-infection with a seconddose administered at 12 hours post-infection for each dose group.Endpoint: 24 hour lung CFU counts. Animals were euthanized via CO₂inhalation, their lungs aseptically removed, homogenized, diluted andplated for CFU determination.Results: The results are summarized in Table 9.

1. A compound having Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X is selectedfrom N and C(R²); each of R¹, R², R³, R⁵ and R⁶ is independentlyselected from hydrogen, halo, —(C₁-C₆ alkyl), —OR^(A),—C(O)NR^(B)R^(B′), NR^(B)R^(B′), S(O)₀₋₂R^(C), —(C₀-C₆alkylene)-carbocyclyl, and —(C₀-C₆ alkylene)-heterocyclyl; or R¹ and R²are optionally taken together with atoms to which they are bound to forma carbocyclyl or heterocyclyl ring; or R² and R³ are optionally takentogether with atoms to which they are bound to form a carbocyclyl orheterocyclyl ring; R⁴ is selected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, and —(C₀-C₆ alkylene)-heterocyclyl; R^(4′) isselected from hydrogen, —(C₂-C₆ alkyl), S(O)₁₋₂R^(C), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆alkyl), and —C(O)—(C₁-C₆ alkyl)-NR^(D)R^(E); or R⁴ and R^(4′) areoptionally taken together with the nitrogen atom to which they arecommonly bound to form a 4-8 membered ring optionally comprising 1-2additional heteroatoms independently selected from N, O and S; R^(6′) isselected from hydrogen, —(C₁-C₆ alkyl) and —(C₃-C₆ cycloalkyl); eachR^(A) is independently selected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)—(C₀-C₆alkylene)-heterocyclyl, and —C(O)N(R^(D))(R^(E)); each R^(B) and eachR^(B′) is independently selected from hydrogen, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl,—C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H,—C(O)—(C₀-C₆ alkylene)-heterocyclyl, and —C(O)—(C₀-C₆alkylene)-N(R^(D))(R^(E)); each R^(C) is independently selected from—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl and —(C₀-C₆alkylene)-heterocyclyl; and each R^(D) and each R^(E) is independentlyselected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl,and —(C₀-C₆ alkylene)-heterocyclyl, wherein: any alkyl, or alkyleneportion of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶ is optionally andindependently substituted with one or more substituents independentlyselected from halo, ═O, OR^(A), NR^(B)R^(B′), and S(O)₀₋₂R^(C); anyalkyl or alkylene portion of R^(6′), R^(A), or R^(C), is optionally andindependently substituted with one or more fluoro; any carbocyclyl orheterocyclyl portion of any of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶, or anyring formed by taking together R¹ and R², R² and R³ or R⁴ and R^(4′) isoptionally and independently substituted on a carbon atom with one ormore substituents independently selected from halo, ═O, C₁-C₄fluoroalkyl, C₁-C₄ alkyl, —(C₀-C₆ alkylene)-(C₃-C₁₀ carbocyclyl),—(C₀-C₆ alkylene)-(4-13 membered heterocyclyl), OR^(A), —(C₀-C₆alkylene)-NR^(B)R^(B′), and S(O)₀₋₂R^(C); any heterocyclyl portion ofany of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶, or any ring formed by takingtogether R¹ and R², R² and R³ or R⁴ and R^(4′) is optionally andindependently substituted on a substitutable nitrogen atom with R^(F);each R^(F) is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₁-C₆ hydroxyalkyl), —(C₀-C₆ alkylene)-carbocyclyl,—(C₀-C₆ alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆ alkyl), —S(O)₁₋₂—(C₀-C₆alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆ alkylene)-heterocyclyl,—C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)H,—C(O)—(C₀-C₆ alkylene)-heterocyclyl, —(C₀-C₆ alkylene)-C(O)₂—(C₁-C₆alkyl), —(C₁-C₆ alkylene)-NR^(B)R^(B′) and —C(O)N(R^(D))(R^(E)); anycarbocyclyl or heterocyclyl portion of R^(A), R^(B), R^(B′), R^(C),R^(D), R^(E), R^(F), any cycloalkyl portion of R^(6′), or anysubstituent of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶ is optionally andindependently substituted on a carbon atom with a one or moresubstituents independently selected from fluoro, chloro, C₁-C₄ alkyl,C₁-C₄ fluoroalkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄ fluoroalkyl, ═O, —OH, —NH₂,—NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; any heterocyclyl portion ofR^(A), R^(B), R^(B′), R^(C), R^(D), R^(E), R^(F), or any heterocyclylsubstituent of R¹, R², R³, R⁴, R^(4′), R⁵, or R⁶ is optionallysubstituted on a substitutable nitrogen atom with —C₁-C₄ alkyl, or—S(O)₁₋₂—(C₁-C₄ alkyl); and the compound is other than:

a salt of any of the foregoing.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: X is selected from Nand C(R²); each of R¹, R², R³, R⁵ and R⁶ is independently selected fromhydrogen, halo, —(C₁-C₆ alkyl), —OR^(A), —C(O)NR^(B)R^(B′),NR^(B)R^(B′), S(O)₀₋₂R^(C), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl; or R¹ and R² are optionally taken together withatoms to which they are bound to form a carbocyclyl or heterocyclylring; or R² and R³ are optionally taken together with atoms to whichthey are bound to form a carbocyclyl or heterocyclyl ring; R⁴ isselected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl,and —(C₀-C₆ alkylene)-heterocyclyl; R^(4′) is selected from hydrogen,—(C₂-C₆ alkyl), S(O)₁₋₂R^(C), —(C₀-C₆ alkylene)-carbocyclyl, —(C₀-C₆alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl), and —C(O)—(C₁-C₆alkyl)-NR^(D)R^(E); or R⁴ and R^(4′) are optionally taken together withthe nitrogen atom to which they are commonly bound to form a 4-8membered ring optionally comprising 1-2 additional heteroatomsindependently selected from N, O and S; R^(6′) is selected fromhydrogen, —(C₁-C₆ alkyl) and —(C₃-C₆ cycloalkyl); each R^(A) isindependently selected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —C(O)—(C₁-C₆alkyl), —C(O)—(C₀-C₆ alkylene)-carbocyclyl, —C(O)—(C₀-C₆alkylene)-heterocyclyl, and —C(O)N(R^(D))(R^(E)); each R^(B) and eachR^(B′) is independently selected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆alkyl), —S(O)₁₋₂—(C₀-C₆ alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆alkylene)-carbocyclyl, —C(O)H, —C(O)—(C₀-C₆ alkylene)-heterocyclyl, and—C(O)N(R^(D))(R^(E)); each R^(C) is independently selected from —(C₁-C₆alkyl), —(C₀-C₆ alkylene)-carbocyclyl and —(C₀-C₆alkylene)-heterocyclyl; and each R^(D) and each R^(E) is independentlyselected from hydrogen, —(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-carbocyclyl,and —(C₀-C₆ alkylene)-heterocyclyl, wherein: any alkyl, or alkyleneportion of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶ is optionally andindependently substituted with one or more substituents independentlyselected from halo, ═O, OR^(A), NR^(B)R^(B′), and S(O)₀₋₂R^(C); anyalkyl or alkylene portion of R^(6′), R^(A), or R^(C), is optionally andindependently substituted with one or more fluoro; any carbocyclyl orheterocyclyl portion of any of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶, or anyring formed by taking together R¹ and R², R² and R³, or R⁴ and R^(4′) isoptionally and independently substituted on a carbon atom with one ormore substituents independently selected from halo, ═O, C₁-C₄fluoroalkyl, C₁-C₄ alkyl, C₃-C₁₀ carbocyclyl, a 4-13 memberedheterocyclyl, OR^(A), NR^(B)R^(B′), and S(O)₀₋₂R^(C); any heterocyclylportion of any of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶, or any ring formed bytaking together R¹ and R², R² and R³, or R⁴ and R^(4′) is optionally andindependently substituted on a substitutable nitrogen atom with R^(F);each R^(F) is independently selected from —(C₁-C₆ alkyl), —(C₀-C₆alkylene)-carbocyclyl, —(C₀-C₆ alkylene)-heterocyclyl, —S(O)₁₋₂—(C₁-C₆alkyl), —S(O)₁₋₂—(C₀-C₆ alkylene)-carbocyclyl, —S(O)₁₋₂—(C₀-C₆alkylene)-heterocyclyl, —C(O)—(C₁-C₆ alkyl), —C(O)—(C₀-C₆alkylene)-carbocyclyl, —C(O)H, —C(O)—(C₀-C₆ alkylene)-heterocyclyl, and—C(O)N(R^(D))(R^(E)); any carbocyclyl or heterocyclyl portion of R^(A),R^(B), R^(B′), R^(C), R^(D), R^(E), R^(F), any cycloalkyl portion ofR^(6′), or any substituent of R¹, R², R³, R⁴, R^(4′), R⁵, R⁶ isoptionally and independently substituted on a carbon atom with a one ormore substituents independently selected from fluoro, chloro, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄ fluoroalkyl, ═O, —OH,—NH₂, —NH(C₁-C₄ alkyl), and —N(C₁-C₄ alkyl)₂; and any heterocyclylportion of R^(A), R^(B), R^(B′), R^(C), R^(D), R^(E), R^(F), or anyheterocyclyl substituent of R¹, R², R³, R⁴, R^(4′), R⁵, or R⁶ isoptionally substituted on a substitutable nitrogen atom with —C₁-C₄alkyl, or —S(O)₁₋₂—(C₁-C₄ alkyl).
 3. The compound of claim 1, whereineach of R⁵, R⁶ and R^(6′) is hydrogen.
 4. The compound of claim 1,wherein: R⁴ is selected from hydrogen and —(C₁-C₆ alkyl); R^(4′) isselected from hydrogen, —(C₂-C₆ alkyl) optionally substituted with oneor more substituents independently selected from hydroxy and halo,—(C₃-C₆ cycloalkyl), —C(O)—(C₁-C₆ alkyl), —C(O)—(C₁-C₆alkylene)-N(R^(D))(R^(E)), and S(O)₁₋₂R^(C); or R⁴ and R^(4′) are takentogether with the nitrogen atom to which they are commonly bound to forma 4-6 membered ring optionally comprising 1-2 additional heteroatomsindependently selected from N, O and S; R^(C) is —(C₁-C₆ alkyl); andeach of R^(D) and R^(E) is independently selected from hydrogen and—(C₁-C₆ alkyl).
 5. The compound of claim 4, wherein: R⁴ is selected fromhydrogen and —(C₁-C₆ alkyl); R^(4′) is selected from hydrogen, —(C₂-C₆alkyl), —(C₃-C₆ cycloalkyl), —C(O)—(C₁-C₆ alkyl), —C(O)—(C₁-C₆alkylene)-N(R^(D))(R^(E)), and S(O)₁₋₂R^(C); R^(C) is —(C₁-C₆ alkyl);and each of R^(D) and R^(E) is independently selected from hydrogen and—(C₁-C₆ alkyl).
 6. The compound of claim 5, wherein: R⁴ is selected fromhydrogen, methyl, ethyl and propyl; and R^(4′) is selected fromhydrogen, ethyl, propyl, cyclopropyl, —C(O)CH₃, —C(O)CH₂N(CH₃)₂, and—S(O)₂CH₃.
 7. The compound of claim 1, wherein R¹ is selected fromhydrogen, halo, —(C₁-C₆ alkyl) optionally substituted with one or moresubstituents independently selected from halo, —NR^(B)R^(B′),—C(O)NR^(B)R^(B′), —OR^(A), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl, wherein R^(A) is C₁-C₆ alkyl optionallysubstituted with one or more fluoro.
 8. The compound of claim 1, whereinR³ is selected from hydrogen and —N(R^(B))(R^(B′)), wherein R^(B) ishydrogen.
 9. The compound of claim 1, wherein X is C(R²).
 10. Thecompound of claim 1, wherein: X is C(R²); and R¹ is selected fromhydrogen, halo, —(C₁-C₆ alkyl) optionally substituted with one or moresubstituents independently selected from halo, —NR^(B)R^(B′),—C(O)NR^(B)R^(B′), —OR^(A), —(C₀-C₆ alkylene)-carbocyclyl, and —(C₀-C₆alkylene)-heterocyclyl, wherein R^(A) is C₁-C₆ alkyl optionallysubstituted with one or more fluoro.
 11. The compound of claim 10,wherein R¹ is selected from hydrogen, halo, —(C₁-C₆ alkyl) optionallysubstituted with one or more substituents independently selected fromhalo, and —OR^(A), wherein R^(A) is C₁-C₆ alkyl optionally substitutedwith one or more fluoro.
 12. The compound of claim 11, wherein R¹ isselected from hydrogen, fluoro, chloro, CF₃, OCH₃, OCF₃, N(CH₃)₂ andNHCH₃.
 13. (canceled)
 14. The compound of claim 1, wherein: X is C(R²);and R¹ and R² are taken together with the atoms to which they are boundto form a nitrogen-containing heterocyclyl ring, wherein the ringcomprising R¹ and R² is optionally substituted on any substitutablenitrogen atom with C₁-C₄ alkyl; and optionally substituted on a carbonatom with NR^(B)R^(B′), wherein each of R^(B) and R^(B′) isindependently selected from hydrogen and C₁-C₆ alkyl.
 15. The compoundof claim 1, wherein: X is C(R²); and R¹ and R² are taken together withthe carbon atoms to which they are bound to form:

wherein “

1” represents a point of attachment to the carbon atom bound to R¹; “

2” represents a point of attachment to the carbon atom bound to R²; andf is 0 or
 1. 16. The compound of claim 14, wherein R¹ and R² are takentogether with the carbon atoms to which they are bound to form:

wherein “

1” represents a point of attachment to the carbon atom bound to R¹ and “

2” represents a point of attachment to the carbon atom bound to R². 17.The compound of claim 1, wherein X is C(R²); and R² is —(C₀-C₆alkylene)-heterocyclyl optionally substituted on a nitrogen atom with—(C₁-C₆ alkyl); —(C₀-C₆ alkylene)-carbocyclyl; or —(C₁-C₆)alkylsubstituted with NR^(B)R^(B′).
 18. The compound of claim 17, wherein R²is pyrrolidinyl optionally substituted on a nitrogen atom with C₁-C₄alkyl or benzyl.
 19. The compound of claim 1, wherein: X is C(R²); andR² and R³ are taken together with the atoms to which they are bound toform a nitrogen-containing heterocyclyl.
 20. The compound of claim 19,wherein R² and R³ are taken together with the atoms to which they arebound to form

wherein “

2” represents a point of attachment to the carbon atom bound to R²; “

3” represents a point of attachment to the carbon atom bound to R³; andf is 0 or
 1. 21. The compound of claim 1, wherein: X is C(R²); and R³ isselected from hydrogen and —N(R^(B))(R^(B′)), wherein R^(B) is hydrogenand R^(B′) is —C(O)—(C₀-C₆ alkylene)-heterocyclyl or —C(O)—(C₀-C₆alkylene)-N(R^(D))(R^(E)).
 22. The compound of claim 21, wherein R³ isselected from hydrogen and


23. The compound of claim 1, wherein X is N.
 24. A compound selectedfrom any one of the following compounds: Compound No. Compound StructureS3-7-1-A (diastereomer A) S3-7-1-B (diastereomer B)

S3-7-2

S3-7-3-A (diastereomer A) S3-7-3-B (diastereomer B)

S3-7-4-A (diastereomer A) S3-7-4-B (diastereomer B)

S3-7-5

S3-7-6-A (diastereomer A) S3-7-6-B (diastereomer B)

S3-7-7-A (diastereomer A) S3-7-7-B (diastereomer B)

S3-7-8-A (diastereomer A) S3-7-8-B (diastereomer B)

S3-7-9-A (diastereomer A) S3-7-9-B (diastereomer B)

S3-7-10-A (diastereomer A) S3-7-10-B (diastereomer B)

S3-7-11

S3-7-12

S3-7-13-A (diastereomer A) S3-7-13-B (diastereomer B)

S4-14-1 (diastereomer A)

S4-14-2 (diastereomer A)

S4-14-3 (diastereomer A)

S4-14-4 (diastereomer A)

S4-14-5-A (diastereomer A) S4-14-5-B (diastereomer B)

S4-14-7 (diastereomer A)

S4-14-8 (diastereomer A)

S4-14-9 (diastereomer A)

S4-14-10 (diastereomer A)

S4-14-11 (diastereomer A)

S4-14-12 (diastereomer A)

S4-14-13 (diastereomer A)

S4-14-14-A (diastereomer A) S4-14-14-B (diastereomer B)

S4-14-16 (diastereomer A)

S4-14-17 (diastereomer A)

S4-14-18 (diastereomer A)

S5-10-1-A (diastereomer A) S5-10-1-B (diastereomer B)

S5-10-1-2-A (diastereomer A) S5-10-1-2-B (diastereomer B)

S5-10-3-A (diastereomer A) S5-10-3-B (diastereomer B)

S5-10-4-A (diastereomer A) S5-10-4-B (diastereomer B)

S6-6-1 (single diastereomer)

S6-6-2 (single diastereomer)

S6-6-3 (single diastereomer)

S7-14-1-A (diastereomer A) S7-14-1-B (diastereomer B)

S7-14-2-A (diastereomer A)

S7-14-3-A (diastereomer A)

S8-4-1

S8-4-2

S8-4-3

S9-4-1

S9-5-1

S9-5-2

S9-5-3

S9-5-4

S9-5-5

S9-5-6

S10-4-1 (single diastereomer)

S10-4-2 (single diastereomer)

S10-4-3 (single diastereomer)

S11-3-1

S11-3-2

S11-3-3

S12-8-1-A (diastereomer A) S12-8-1-B (diastereomer B)

S12-8-2-A (diastereomer A)

S12-8-3-A (diastereomer A) S12-8-3-B) (diastereomer A)

S12-8-4-A (diastereomer A)

S12-8-5-A (diastereomer A)

S12-8-6-A (diastereomer A) S12-8-6-B (diastereomer B)

S12-8-7-A (diastereomer A)

S12-8-8-A (diastereomer A)

S13-5-1

S13-5-2

S14-8-1

S14-8-2

S14-8-3-A (diastereomer A) S14-8-3-B (diastereomer B)

S15-10-1

S15-10-2

S15-10-3-A (diastereomer A) S15-10-3-B (diastereomer B)

S16-7-1 (single diastereomer)

S16-7-2 (single diastereomer)

S16-7-3 (single diastereomer)

S16-7-4 (single diastereomer)

S16-7-5 (single diastereomer)

S16-7-6 (single diastereomer)

S17-3-1

S17-3-2

S17-3-3

S17-3-4

S17-3-5

S17-3-6

S17-3-7

S17-3-8

S17-3-9

S17-3-10

S17-3-11

S18-5-1-1

S18-5-1-2

S18-5-2-1

S18-5-2-2

S19-7-1-B (diastereomer B)

S19-7-2

S19-7-3-A (diastereomer A) S19-7-3-B (diastereomer B)

S19-7-4-A (diastereomer A) S19-7-4-B (diastereomer B)

S19-7-5-A (diastereomer A) S19-7-5-B (diastereomer B)

S19-7-6

S19-7-7-A (diastereomer A) S19-7-7-B (diastereomer B)

S20-4-1 (single diastereomer)

S20-4-2 (single diastereomer)

S20-4-3 (single diastereomer)

S20-4-4 (single diastereomer)

S21-5-1

S21-5-2

S21-5-3

S21-5-4

or a pharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a compound of claim
 1. 26. A method for treating or preventing aninfection or colonization in a subject comprising administering to thesubject an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof. 27-60. (canceled)